Pharmaceutical composition and the use thereof, and application regime of said pharmaceutical composition for on-demand contraception

ABSTRACT

The invention relates to a pharmaceutical composition for non-hormonal, on-demand contraception and to processes for preparing this pharmaceutical composition. The latter comprises 2H-indazole as novel EP2 receptor antagonists in combination with COX inhibitors. The invention furthermore provides a method for non-hormonal female-controlled on-demand contraception where a pharmaceutical composition comprising EP2 receptor antagonists in combination with COX inhibitors is taken on demand prior to expected sexual intercourse.

The present invention relates to the subject matter stated in the patentclaims, i.e.:

(a) the use of a pharmaceutical composition comprising at least one2H-indazole as novel EP2 receptor antagonist according to generalformula I and at least one cyclooxygenase inhibitor (COX inhibitor) fornon-hormonal on-demand contraception and contraception,

(b) a pharmaceutical composition comprising at least one 2H-indazole asnovel EP2 receptor antagonist according to general formula Ia and atleast one (COX inhibitor) and

(c) the use of at least one EP2 receptor antagonist according to generalformula Ia in combination with at least one COX inhibitor for preparinga pharmaceutical composition, and also processes for preparing thispharmaceutical composition and its use for non-hormonal on-demandcontraception and fertility control.

DESCRIPTION OF THE INVENTION

Hormonal contraception with daily orally administered low dosages ofsynthetic gestagens and oestrogens is, in addition to administration ofa gestagen via an intrauterine system (IUS) such as Mirena®, currentlythe method showing best pharmacological efficacy in the prevention ofpregnancies in clinical studies. Oral contraception requires continuousregular intake of hormone-containing pills, independent of the frequencyof sexual intercourse and thus the necessity of contraceptiveprotection. Women having infrequent sexual intercourse are thus exposedto hormones for an unnecessarily long period of time. Especially forthis group of users, there is therefore a need for a preparation whichcan be taken only when required shortly before or optionally alsoimmediately after intercourse but, at the same time, offers a(contraceptive) protection similar to that of the classic oralcontraceptives.

Although there has been such a need for decades (Canzler et al. Zbl.Gynäkol.; (1984); 106:1182-1191), there is hitherto no preparationallowing contraception on demand (alternatively also referred to in theliterature as on-demand contraception, fertility control on demand orprecoital contraception) (Aitken et al. Contraception; (2008); 78:p.28-p.35). In a study carried out in Ghana, it has been reported thatwoman use Primolut-N tablets comprising 5 mg of norethisterone, whichare approved for the treatment of various gynaecological disorders ason-demand contraceptive in 94% of cases and for the treatment ofmenstrual disorders in only 6% of cases (Opare-Addo et al. Afr. J.Reprod. Health.; (2011); 15(1):65-7). Anecdotal reports and datacollected by Family Health International confirm that women in manyemerging countries and South American and Africa, but also in countriessuch as Great Britain, deliberately use preparations developed foremergency contraception also for on-demand contraception.

Products approved for emergency contraception are Postinor®, Plan B® andLevonelle® (single administration of 1.5 mg of levonorgestrel (LNG)within 72 hours) and ellaOne® (single administration of 30 mg ofulipristal acetate (UPA) within 120 h after sexual intercourse). Thesepreparations are described, for example, in the application EP 1448207(LNG) and in the applications WO2011/069871 and WO2011/091892 (UPA).Levonorgestrel is a progesterone derivative, and ulipristal acetate is aselective progesterone receptor modulator. Thus, both are hormonalmethods employed in very high doses compared to a hormone-comprisingoral contraceptive taken regularly. Thus, for example, administration ofa single dose of 1.5 mg of LNG corresponds to 10 times the amount thatis administered daily when an LNG-containing pill (such as Microgynon®)is taken regularly. In Europe, the mini pill Microlut®, which contains0.03 mg of LNG and is taken for a period of 28 days, which correspondsto a dose of only 0.84 mg of LNG per cycle, has been approved. Here, thesingle dose of 1.5 mg of LNG for emergency contraception corresponds tomore than two monthly doses of Microlut®. If a pill developed foremergency contraception is used several times a month, the dose is,correspondingly, even higher. Raymond et al. have shown that even singleadministration may have effects on the cycle (Raymond et al. ObstetGynecol.; (2011); 117(3):673-81). In addition, these preparations foremergency contraception do not have the same contraceptive reliabilityas a hormone-containing oral contraceptive taken regularly; however,this would be desirable for on-demand contraception. Evaluation ofdifferent studies for pre- and postcoital use of 0.75 mg of LNG showed aPearl Index of 5.1 [pregnancies per 100 woman years] (95% confidenceinterval [CI] 3.8-6.7), which represents moderate efficacy (Raymond etal. Obstet Gynecol.; (2011); 117(3):673-81).

Hitherto, for on-demand contraception, only hormonal methods have beendescribed; however, none of these has yet been approved:

WO 2010/119030 describes an on-demand preparation where, as gestagen,levonorgestrel or norgestrel is used in a dose range of from 0.5 to 1.5mg, with the preparation to be used 24 hours prior to intercourse.However, the dose of LNG corresponds to the dose used for emergencycontraception.

WO2007/045513 describes a method for on-demand contraception where agestagen is, if required, administered transdermally using a patch.

WO96/12494 uses competitive progesterone antagonists for on-demandcontraception.

WO2010/119029 describes progesterone or progesterone receptor modulatorsfor on-demand contraception which are administered within 72 hours priorto expected sexual intercourse. Here, 30 mg of UPA are employed onceprior to sexual intercourse, which corresponds to the dose used foremergency contraception.

Non-hormonal methods for on-demand contraception have not yet beendescribed. However, there is a need for non-hormonal pharmacologicalmethods for women who, for medicinal or personal reasons, do not want touse or cannot use hormonal contraceptives. A further advantage of anon-hormonal approach is the fact that the menstrual cycle is notaffected.

It has already long been known that prostaglandins are key molecules inthe processes of female reproductive biology, such as for example theregulation of ovulation and fertilization. The effects of theprostaglandins are mediated through their G protein coupled receptors,which are located in the cell membrane. Of particular interest isprostaglandin E2 (PGE2), which effects a great variety of cellularactions by binding to functionally different receptor subtypes, namelythe EP₁, EP₂, EP₃ and EP₄ receptors. The receptor subtypes to whichprostaglandin E₂ binds are of particular importance for thereceptor-mediated actions which are involved in the regulation offertility. Thus it could be shown that the reproductive functions areimpaired in EP2 knockout mice (EP2^(−/−)), e.g. in mice which no longerhave a functional PGE₂ receptor subtype EP2, and that these animals havea smaller number of offspring per pregnancy (Matsumoto et al. Biology ofReproduction; (2001); 64: 1557-1565). Likewise it could be shown thatthese EP2 knockout mice (Hizaki et al. Proc Natl Acad Sci U.S.A.;(1999); 96(18):10501-10506) display markedly decreased cumulus expansionand severe subfertility, which is to be regarded as being causallylinked with decreased reproductive processes such as ovulation andfertilization. Accordingly, the EP2 receptor is an important target forthe development of drugs for the regulation of female fertility.

The application DE 10 2009 049 662 A1 describes 2-5-disubstituted2H-indazoles which, with high binding affinity, selectively antagonizethe EP2 receptor. These EP2 receptor antagonists are disclosed interalia for use as contraceptive, but not for on-demand contraception.

In a pairing study with cynomolgus monkey, it was shown that an EP2receptor antagonist administered continuously has a subfertile effect(Peluffo et al. 2012, Annual Meeting of the American Society forReproductive Medicine). However, continuous administration does notcorrespond to use for on-demand contraception.

The applications of Summit Corporation Plc. (WO2007/091107), C M Sun etal. (WO2008/070599) and Janssen Pharmaceutica NV (WO2010/124102)describe 2H-indazoles. The compounds disclosed in WO2007/091107 interactwith the utropine A promoter and are claimed for the treatment ofDuchenne muscular dystrophy, Becker muscular dystrophy or cachexia.WO2008/070599 describes compounds binding to the VGEFR-3 receptor. Theyare claimed for the treatment of cancer. The compounds described in theapplication WO2010/124102 inhibit monoacylglycerol lipase (MGL) and areclaimed for the treatment of inflammatory pain. None of the threeapplications mentioned discloses whether the compounds bind to the EP2receptor and are suitable for fertility control.

The effect of COX inhibitors on female ovulation has been investigatedby several research groups. Thus, Pall et al. examined the effect ofrofecoxib on ovulation (Pall et al.; Human Reproduction; (2001);16(7):1323-1328). In this study, 25 mg of the active compound were usedon 9 successive days. In 4 of 6 patients, ovulation was delayed by morethan 48 hours.

Edelmann et al. 2013 examined the effect of the daily oraladministration of 400 mg of celecoxib on ovulation. Depending on timeand duration of administration, an increase in ovulatory dysfunction of25-30% was observed. The ovulatory dysfunction was characterized by aflattened LH (luteinizing hormone) peak and/or by anovulation (Edelmannet al. Contraception. (2013); 87(3):352-357). In 2010, Edelmann et al.had already shown that daily administration of 400 mg of celecoxib overthe entire cycle increased the cycle length from 27.2+/−2.4 days to28.5+/−2.5 days and changed time and height of the LH peak (Edelmann etal. Contraception; (2010); 81(6):496-500). Both results showed that thebenefit of celecoxib for emergency contraception is limited.

In a pilot study with 6 women treated with 3×50 mg of indomethacin perday for at least 3 days, it was shown that administration ofindomethacin delayed ovulation by 2-12 days in 5 cases. The treatmentwas initiated when the dominant follicle had reached a maximum sizeof >16 mm or LH was detected in the urine (Athanasious et al. FertilSteril.; (1996); 65(3): 556-60). This study also confirmed the resultsby Killick S and Elstein M. 1987 where indomethacin administered in adose of 2×100 mg per day over 5 days led to inhibition of ovulation(Killick S and Elstein M. Fertil Steril.; (1987); 47(5):773-7).

A clinical study by Bata et al. 2006 showed that administration ofmeloxicam reversibly delayed ovulation by 5 days (Bata et al., J ClinPharmacol (2006); 46:925-932). This result was confirmed by Jesam et al.2010 (Jesam et al. Hum Reprod.; (2010); 25(2):368-73). In this clinicalstudy, 30 mg or 15 mg of meloxicam were administered daily over a periodof 5 days during the late follicular phase. In 90.9% (30 mg meloxicamgroup) or 50.0% (15 mg meloxicam group), ovulation was abnormal, whichshows that meloxicam may be suitable for emergency contraception.

In principle, COX inhibitors are known to be relatively well tolerated;however, Castellsague et al. 2012 and Varas-Lorenzo et al. 2013indicated that there is an increased risk of cardiovascular andgastrointestinal events for this class of substances. It is thereforerecommended to use a relatively low dosage (Castellsague et al. DrugSaf.; (2012); 35(12):1127-46; Varas-Lorenzo et al. PharmacoepidemiolDrug Saf.; (2013); doi: 10.1002/pds. 3437. [Epub ahead of print]).

In a pilot study, Massai et al. 2007 examined the use of meloxicam incombination with levonorgestrel (LNG) on the time of ovulation inconnection with emergency contraception (Massai et el. HumanReproduction; (2007) 22(2):434-439). In this study, 2 tablets of in eachcase 0.75 mg of LNG (known inter alia by the trade name Postinor-2) wereadministered on their own or together with 15 mg of meloxicam. In thetreatment group which received the combination of meloxicam and LNG,there was a trend to reduced frequency of ovulation compared to thegroup treated exclusively with LNG. This effect was increasinglypronounced the later the tablets were taken relative to the time ofovulation.

In WO2010/149273 (Bayer Pharma AG), it was shown that a low dose oflevonorgestrel which, on its own, does not inhibit ovulation, mayachieve virtually complete suppression of ovulation in the rat whencombined with piroxicam. However, this approach comprises, in additionto the non-hormonally acting COX inhibitor, a hormonal component in theform of levonorgestrel and does therefore not represent a non-hormonalalternative to purely hormonal approaches.

Accordingly, it is an object of the present invention to provide amethod and a pharmaceutical composition for on-demand contraceptionbased on a pharmacological non-hormonal approach and thus providing analternative to hormonal methods.

In accordance with the invention, this object is achieved by using anon-hormonal pharmaceutical composition comprising at least one EP2receptor antagonist according to formula I and at least one COXinhibitor. In addition, this object is achieved by the pharmaceuticalcomposition itself which comprises at least one EP2 receptor antagonistaccording to formula Ia and at least one COX inhibitor.

The EP2 receptor antagonists according to formula I or Ia according tothe invention have already been described in the patent applicationPCT/EP2012/073556, unpublished at the priority date of the presentapplication. There, they are claimed inter alia for use forcontraception and emergency contraception. In addition, a pharmaceuticalcomposition comprising at least one EP2 receptor antagonist of formula Iand at least one COX inhibitor and its use for contraception aredescribed.

In the patent application PCT/EP2012/073556, it was shown that the EP2receptor antagonists according to formula I or Ia have an antagonisticaction at the EP2 receptor (see biological examples; Table 1) and arethus suitable for fertility control (see biological examples; Tables 2,3 and 4). In the present application, in accordance with the invention,it was possible, by combining the EP2 receptor antagonists according toformula I or Ia with a COX inhibitor, to achieve the contraceptiveaction of the EP2 receptor antagonists or the COX inhibitorssurprisingly even at a still ineffective dose of the individual activecompounds (see biological examples; Tables 6.1-6.5 and 7.1). Thus, thecombination of EP2 receptor antagonists according to general formula Ior Ia with COX inhibitors allows both the dose of the COX inhibitor andthe dose of the EP2 receptor antagonists to be reduced, which in turnreduces possible side effects and thus increases acceptance and safetyof the method.

In addition, the contraceptive action was, surprisingly, achieved evenafter single administration of an EP2 receptor antagonist according togeneral formula I or Ia in combination with a COX inhibitor shortlybefore sexual intercourse (see biological examples; Tables 6.1-6.5 and7.1). This shows that EP2 receptor antagonists in combination with COXinhibitors constitute an effective pharmaceutical composition foron-demand contraception which can be administered before or shortlyafter expected sexual intercourse. Since this pharmaceutical compositionis non-hormonal, it represents an alternative to hormonal approaches.

In the pre-ovulatory antral follicle, the oocyte is surrounded bycumulus cells which form a dense cell crown around the oocyte. After theLH peak (luteinizing hormone), a series of processes is activated, whichresults in a marked morphological change in this cell crown of cumuluscells. During this, the cumulus cells form an extracellular matrix,which leads to the so-called cumulus expansion (Vanderhyden et al. DevBiol.; (1990); 140(2):307-317). This cumulus expansion is an importantcomponent of the ovulatory process and the subsequent possibility offertilization.

During the cumulus expansion, prostaglandins and here prostaglandin E₂,synthesis whereof is induced by the LH peak, are of decisive importance.Prostanoid EP2 knockout mice (Hizaki et al. Proc Natl Acad Sci USA.;(1999) 96(18):10501-10506.) show a markedly decreased cumulus expansionand severe subfertility, which demonstrates the importance of theprostanoid EP2 receptor for this process.

The anti-ovulatory action of COX inhibitors in humans has beendemonstrated in clinical studies (as described above). COX inhibitorslead to reduced prostaglandin synthesis. In COX-2 knockout mice, it wasshown that prostaglandins play a role in particular in processes ofovulation, cumulus expansion and fertilization (Cheng J G and Stewart CL. Biol Reprod.; (2003); 68(2):401-4; Lim et al. Cell; (1997)91(2):197-208).

Since, within the prostaglandin pathway, the EP2 receptor is inhibiteddirectly by the EP2 receptor antagonists, the onset of action by thisclass of substances is earlier than the onset of action of COXinhibitors, where the action is triggered by lowering of prostaglandinconcentrations.

On-Demand Contraception or Contraception on Demand

On-demand contraception, fertility control on demand, precoitalcontraception or contraception on demand all refer to the on-demand useof one or more substances for preventing unwanted pregnancy. Theadministration can be before or shortly after expected sexualintercourse. Here, on-demand does not mean optional. Rather, thesubstance/substances has/have to be administered to prevent unwantedpregnancy.

The invention provides the use of a pharmaceutical compositioncomprising (a) at least one EP2 receptor antagonist according to formula(I)

wherein

-   R¹: means H, C₁-C₂ alkyl or C₁-C₂ alkyloxy;-   R²: H or methyl;    subject to the proviso that one of the two residues R¹ or R² equals    H;-   X: —(CH₂)_(l)—, —(CH₂)_(k)—O—, —CH₂—S—, CH₂—S(O)₂—, —CH(CH₃)—,    —CH(CH₃)—O— or —C(CH₃)₂—O—;-   k: 1 or 2;-   l: 0, 1 or 2;-   R⁴: H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, or CH₂—C₃-C₄ cycloalkyl;    -   and in the case that X means (CH₂)_(l)— with l meaning 0 or 1 or        —CH(CH₃)—-   R⁴: additionally a 4-6-membered heterocyclyl residue;    and in the case that X means —(CH₂)_(l)— or —CH(CH₃)—-   R⁴: additionally CN;-   m: 1 or 2;-   n: 1 or 2;-   Ar: a 6-10-membered aryl or 5-10-membered hetaryl residue,-   R³: halogen, CN, SF₅, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₄-C₆    heterocyclyl, O—C₁-C₄ alkyl, O—C₃-C₆ cycloalkyl, O—C₄-C₆    heterocyclyl, S—C₁-C₄ alkyl, S(O)₂—C₁-C₄ alkyl, Ar′, O—Ar′,    C(CH₃)₂—CN or C(CH₃)₂—OH;-   Ar′: an optionally singly or doubly substituted 6-membered aryl or    5-6-membered heteroaryl residue;    wherein the substituents are selected from F, Cl, CN, C₁-C₄ alkyl,    O—C₁-C₄ alkyl, C(CH₃)₂—CN, C(CH₃)₂—OH and C(O)NH₂;    and comprising (b) at least one COX inhibitor selected from the list    below:-   C1 indomethacin;-   C2 diclofenac;-   C4 naproxen;-   C5 ibuprofen;-   C6 meloxicam;-   C7 piroxicam;-   C8 nimesulide;-   C9 ketoprofen;-   C10 tenoxicam;-   C11 mefanemic acid;-   C12 ketoralac;-   C13    celecoxib(4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulphonamide);-   C14    parecoxib(N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulphonylpropionamide);-   C15 rofecoxib (4-(4-mesylphenyl)-3-phenylfuran-2(5H)-one);-   C16 valdecoxib    (4-[5-methyl-3-phenyl-4-isoxazoyl)benzenesulphonamide);-   C17 etoricoxib    for on-demand contraception.

The invention furthermore provides the use of a pharmaceuticalcomposition comprising (a) at least one EP2 receptor antagonistaccording to formula (I), where

-   R¹: means H, C₁-C₂ alkyl or C₁-C₂ alkyloxy;-   R²: H or methyl;    subject to the proviso that one of the two residues R¹ or R² equals    H;-   X: —(CH₂)_(l)—, —(CH₂)_(k)—O—, —CH₂—S—, CH₂—S(O)₂—, —CH(CH₃)—,    —CH(CH₃)—O— or —C(CH₃)₂—O—;-   k: 1 or 2;-   l: 0, 1 or 2;-   R⁴: H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, or CH₂—C₃-C₄ cycloalkyl;    -   and in the case that X means (CH₂)_(l)— with l meaning 0-   R⁴: additionally a 4-6-membered heterocyclyl residue linked via a    ring carbon atom;-   m: 1 or 2;-   n: 1 or 2;-   Ar: a 6-10-membered aryl or 5-10-membered hetaryl residue,-   R³: halogen, CN, SF₅, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₄-C₆    heterocyclyl, O—C₁-C₄ alkyl, O—C₃-C₆ cycloalkyl, O—C₄-C₆    heterocyclyl, S—C₁-C₄ alkyl, S(O)₂—C₁-C₄ alkyl, Ar′, O—Ar′,    C(CH₃)₂—CN or C(CH₃)₂—OH;-   Ar′: an optionally singly or doubly substituted 6-membered aryl or    5-6-membered heteroaryl residue;    wherein the substituents are selected from F, Cl, CN, C₁-C₄ alkyl,    O—C₁-C₄ alkyl, C(CH₃)₂—CN, C(CH₃)₂—OH and C(O)NH₂;    and comprising (b) at least one COX inhibitor selected from the list    above (COX inhibitors C₁-C₁₇) for on-demand contraception.

The 2H-indazoles according to the invention have an antagonistic actionon the EP2 receptor.

C₁-C₂ alkyl or C₁-C₄ alkyl should each be understood to mean a linear orbranched alkyl residue, such as for example methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

The alkyl residues can optionally be singly or multiply substituted withfluorine.

The hydrogen atoms can optionally be replaced by deuterium.

C₁-C₂ alkoxy or C₁-C₄ alkoxy should be understood to mean a linear orbranched residue of the formula alkyl-O—, such as for example methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy ortert-butyloxy.

The alkoxy residues can optionally be singly or multiply substitutedwith fluorine.

C₃-C₆ cycloalkyl should be understood to mean monocyclic alkyl ringssuch as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The cycloalkyl residues can optionally be singly or multiply substitutedwith fluorine.

4-6-membered heterocyclyl should be understood to mean monocyclic ringswhich instead of the carbon atoms contain one or more hetero atoms, suchas oxygen, sulphur and/or nitrogen or a hetero group such as —S(O)— or—SO₂—. The linking bond can be at any carbon atom or at a nitrogen atom.

For example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,1,4-diazepanyl, morpholinyl, thiomorpholinyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl and2-oxo-oxazolidinyl may be mentioned.

The heterocyclyl residues can optionally be singly or multiplysubstituted with fluorine, hydroxy, methoxy or with oxo.

Halogen should in each case be understood to mean fluorine, chlorine,bromine or iodine.

The C₆-C₁₀-membered aryl residue in each case comprises 6-10 carbonatoms and can be benzo-condensed. Phenyl and naphthyl may be mentioned.

The C₆-C₁₀-membered aryl residue can optionally be singly substitutedwith fluorine, chlorine or a methyl group.

The C₅-C₁₀ heteroaryl residue should be understood to mean mono- orbicyclic ring systems which each contain 5-10 ring atoms and whichinstead of the carbon can contain one or more identical or differenthetero atoms, such as oxygen, sulphur or nitrogen. The linking bond canbe at any carbon atom or at a nitrogen atom.

For example, thienyl, thiazolyl, furyl, pyrrolyl, oxazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, phthalidyl, thiophthalidyl, indolyl, isoindolyl, indazolyl,benzothiazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl,azocinyl, indolizinyl, purinyl, isoquinolinyl, quinolinyl, quinolizinyl,quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or1,8-naphthyridinyl and pteridinyl may be mentioned.

The C₅-C₁₀-membered heteroaryl residue can optionally be singlysubstituted by fluorine, chlorine or a methyl group.

If radicals in the compounds according to the invention are substituted,the radicals can, unless specified otherwise, be mono- orpolysubstituted. In the context of the present invention it applies thatfor all radicals which occur multiple times, their meanings areindependent of one another. Substitution with one, two or threeidentical or different substituents is preferred. Substitution with onesubstituent is very particularly preferred.

If a basic functional group is contained, the physiologically compatiblesalts of organic and inorganic acids, such as inter alia hydrochloricacid, sulphuric acid, phosphoric acid, citric acid and tartaric acid,are suitable.

Pharmaceutical Composition Comprising at Least One EP2 ReceptorAntagonist According to General Formula Ia and at Least One COXInhibitor

The present invention provides a pharmaceutical composition comprising(a) at least one EP2 receptor antagonist according to the formula (Ia)and (b) at least one COX inhibitor.

The present invention furthermore provides the use of at least one EP2receptor antagonist of the general formula Ia together with at least oneCOX inhibitor for preparing a medicament or a pharmaceutical compositioncomprising suitable formulation auxiliaries and carriers.

EP2 Receptor Antagonists which, According to the Invention, areComprised in the Pharmaceutical Composition

EP2 receptor antagonists according to the invention which are comprisedin the pharmaceutical composition according to the invention are2H-indazoles of the general formula Ia, where

-   R¹, R²: mean H or methyl;    subject to the proviso that one of the two residues R¹ or R² equals    H;-   X: —(CH₂)_(l)— or —(CH₂)_(k)—O—;-   k: 1 or 2;-   l: 0, 1 or 2;-   R⁴: H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl or CH₂—C₃-C₄ cycloalkyl;-   m: 1 or 2;-   n: 1 or 2;-   Ar: a 6-10-membered aryl or 5-10-membered hetaryl residue,-   R³: halogen, CN, SF₅, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₄-C₆    heterocyclyl, O—C₁-C₄ alkyl, O—C₃-C₆ cycloalkyl, O—C₄-C₆    heterocyclyl, S—C₁-C₄ alkyl, S(O)₂—C₁-C₄ alkyl, Ar′, O—Ar′,    C(CH₃)₂—CN or C(CH₃)₂—OH; and-   Ar′: an optionally singly or doubly substituted 6-membered aryl or    5-6-membered heteroaryl residue;    wherein the substituents are selected from F, Cl, CN, C₁-C₄ alkyl,    O—C₁-C₄ alkyl, C(CH₃)₂—CN, C(CH₃)₂—OH and C(O)NH₂;    and salts, solvates or solvates of the salts thereof, and isomers,    diastereomers, enantiomers and salts or cyclodextrin clathrates    thereof, for producing medicaments which overcome the known    disadvantages and have improved properties such as good in-vivo    efficacy, good solubility and stability.

The compounds according to the invention have an antagonistic action atthe EP2 receptor.

The radicals and substituents have the same meaning as described abovefor the EP2 receptor antagonists of the general formula I.

Preferred are compounds of the formula Ia, wherein

-   R¹: means a methyl group;-   R²: H;-   X: —(CH₂)_(l)— or —(CH₂)_(k)—O—;-   k: 1;-   l: 0 or 1;-   R⁴: C₁-C₄ alkyl, C₃-C₄ cycloalkyl or CH₂—C₃-C₄ cycloalkyl;-   m, n: 2;-   Ar: a phenyl residue;    and salts, solvates or solvates of the salts thereof, and isomers,    diastereomers, enantiomers and salts or cyclodextrin clathrates    thereof, for producing medicaments which overcome the known    disadvantages and have improved properties such as good in-vivo    efficacy, good solubility and stability.

Also preferred are compounds of the formula Ia, wherein

-   R¹: means a methyl group;-   R²: H;-   X: —(CH₂)_(l)— or —(CH₂)_(k)—O—;-   k: 1;-   l: 0 or 1;-   R⁴: C₁-C₄ alkyl, C₃-C₄ cycloalkyl or CH₂—C₃-C₄ cycloalkyl;-   m, n: 1;-   Ar: a phenyl residue;    and salts, solvates or solvates of the salts thereof, and isomers,    diastereomers, enantiomers and salts or cyclodextrin clathrates    thereof, for producing medicaments which overcome the known    disadvantages and have improved properties such as good in-vivo    efficacy, good solubility and stability.

The following EP2 receptor antagonists according to the invention areparticularly preferred:

-   E1    2-{[1-(4-cyano-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E2    2-{[1-(4-tert-butoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E3    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E4    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-morpholinobenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E5    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E6    2-{[1-(2-fluoro-4-mesylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E7 2-{[1-(2-fluoro-4-methoxybenzo    yl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E8    2-{[1-(4-bromo-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E9    2-{[1-(2-fluoro-4-methylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E10    2-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E11    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E12    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E13    2-({1-[4-(4-chlorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E14    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4-methylphenoxy)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E15    2-({1-[4-(4-tert-butylphenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E16    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E17    N-(2-methoxyethyl)-2-({1-[4-(4-methoxyphenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E18    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E19    2-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E20    2-{[1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E21    2-{[1-(4-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E22    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E23    2-{[1-(2-methoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E24    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphonyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E25    N-(2-methoxyethyl)-4-methyl-2-{1-[3-(trifluoromethyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E26    N-(2-methoxyethyl)-4-methyl-2-{[1-(3-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E27    2-{[1-(3-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E28    2-({1-[4-(4-carbamoylphenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E29    2-({1-[4-(cyclopentyloxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E30    2-({1-[4-(difluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E31    2-{[1-(4-cyanobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E32    2-({1-[4-(1H-imidazol-1-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E33    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(oxazol-2-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E34    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(oxazol-5-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E35    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(isoxazol-5-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E36    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(1H-pyrazol-1-yl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E37    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(1H-1,2,4-triazol-1-yl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E38    2-({1-[4-(difluoromethoxy)-2-fluorobenzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E39    2-({1-[2-fluoro-4-(pyrrolidin-1-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E40    2-({1-[(3,4′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E41    2-({1-[(3-fluoro-4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E42    2-({1-[(3-fluoro-4′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E43    2-[(1-{[3-fluoro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E44    2-[(1-{[3-fluoro-2′-(trifluoromethoxy)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E45    2-({1-[(2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E46    2-({1-[(2′,4′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E47    2-({1-[(2-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E48    N-(2-methoxyethyl)-4-methyl-2-({1-[(2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E49    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4-pyridyloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E50    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4H-1,2,4-triazol-4-yl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E51    2-({1-[2-fluoro-4-[morpholin-4-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E52    2-{[1-(4-bromobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E53    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E54    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E55    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E56    4-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E57    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E58    4-methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E59    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide-   E60    N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]-methyl}-2H-indazole-5-carboxamide-   E61    N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}-methyl)-4-methyl-2H-indazole-5-carboxamide-   E62    N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E63    N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E64    2-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide-   E65    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-carboxamide-   E66    4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-N-[2-(2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-carboxamide-   E67    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxylethyl]-2H-indazole-5-carboxamide-   E68    4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-({1-[4-(trifluoromethyl)benzoyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E69    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide-   E70    2-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoro-ethoxy)ethyl]-2H-indazole-5-carboxamide-   E71    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E72    N-(2-isopropoxyethyl)-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E73    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E74    N-(2-isopropoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E75    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E76    2-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E77    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide-   E78    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoro-methoxy)ethyl]-2H-indazole-5-carboxamide-   E79    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide-   E80    4-methyl-N-[2-(trifluoromethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E81    N-(2-tert-butoxyethyl)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carboxamide-   E82    N-(2-tert-butoxyethyl)-2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E83    N-(2-tert-butoxyethyl)-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E84    N-(2-tert-butoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E85    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-{2-[(²H3)methyloxy]-(²H4)ethyl}-2H-indazole-5-carboxamide-   E86    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-{2-[(²H3)methyloxy](²H4)ethyl}-2H-indazole-5-carboxamide-   E87    2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E88    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide-   E89    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}-methyl)-2H-indazole-5-carboxamide-   E90    2-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E91    2-{[1-(4-chloro-2-fluorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E92    2-({1-[3-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E93    2-({1-[4-chloro-3-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E94    2-{[1-(4-cyclopropylbenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E95    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide-   E96    2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E97    4-methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}-methyl)-2H-indazole-5-carboxamide-   E98    2-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E99    4-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]azetidin-3-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E100    N-[2-(cyclopropyloxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide-   E101    N-[2-(cyclobutyloxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide-   E102    2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide-   E103    N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}-methyl)-4-methyl-2H-indazole-5-carboxamide-   E104    N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzoyl)azetidin-3-yl]-methyl}-2H-indazole-5-carboxamide-   E105    2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide-   E106    N-(2-tert-butoxyethyl)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-2H-indazole-5-carboxamide-   E107    N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E108    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E109    2-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E110    2-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E111    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E112    2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-carboxamide-   E113    4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide-   E114    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-azetidin-3-yl)methyl]-2H-indazole-5-carboxamide-   E115    2-({1-[4-(4-chlorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide-   E116    2-({1-[4-(4-chlorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E117    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)-azetidin-3-yl]methyl}-2H-indazole-5-carboxamide-   E118    4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)azetidin-3-yl]methyl}-2H-indazole-5-carboxamide-   E119    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-ethyl-4-methyl-2H-indazole-5-carboxamide-   E120    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide-   E121    2-({1-[4-(4-chlorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide-   E122    4-methyl-2-({1-[4-(4-methylphenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E123    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E124    4-methyl-2-{[1-(4-morpholinobenzoyl)piperidin-4-yl]methyl}-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E125    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E126    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E127    4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E128    4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E129    4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E130    2-({1-[4-(4-cyanophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide-   E131    2-({1-[4-(3-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide-   E132    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E133    2-[(1-{4-[(5-cyanopyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E134    2-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E135    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[5-(trifluoromethyl)pyridin-2-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E136    2-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E137    2-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E138    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{[4′-(trifluoromethyl)biphenyl-4-yl]carbonyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E139    2-{[1-(4-bromobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E140    2-({1-[4-(5-chloropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E141    2-({1-[(4′-methoxy-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E142    4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E143    2-({1-[(4′-fluoro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E144    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E145    2-({1-[4-(6-methoxypyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E146    2-({1-[4-(6-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E147    4-methyl-2-({1-[4-(5-methylpyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E148    2-({1-[4-(5-fluoropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E149    2-({1-[4-(5-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E150    4-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E151    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E152    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E153    2-({1-[4-(4-cyanophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E154    2-{[1-(4-bromo-3-methylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E155    2-{[1-(4-tert-butylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E156    2-({1-[4-(1-hydroxy-1-methylethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E157    2-{[1-(4-cyclohexylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E158    2-({1-[4-(1-cyano-1-methylethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E159    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E160    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-3-yloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E161    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E162    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E163    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E164    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzoyl)-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E165    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E166    2-({1-[(4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E167    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E168    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E169    2-[(1-{4-[(5-cyanopyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E170    2-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E171    2-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E172    2-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E173    N-(2-methoxyethyl)-4-methyl-2-[(1-{[4′-(trifluoromethyl)biphenyl-4-yl]carbonyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E174    2-({1-[4-(3-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E175    2-{[1-(2-fluoro-4-isopropoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E176    2-({1-[(3-fluoro-3′,4′-dimethylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E177    2-({1-[(2′,3-difluoro-4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E178    2-({1-[4-(difluoromethoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E179    2-({1-[4-(2-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E180    2-({1-[(4′-cyano-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E181    2-({1-[4-(5-chloropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E182    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E183    N-(2-methoxyethyl)-2-({1-[(4′-methoxy-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E184    2-({1-[(4′-chloro-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E185    2-[(1-{[4′-(2-cyanopropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E186    N-(2-methoxyethyl)-2-({1-[4-(5-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E187    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E188    N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E189    2-({1-[(4′-fluoro-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E190    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E191    N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E192    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E193    2-({1-[(4′-fluoro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E194    2-({1-[(4′-chloro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E195    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E196    2-({1-[(4′-chloro-2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E197    2-({1-[(2′-chloro-4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E198    2-({1-[4-(5-chloropyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E199    2-({1-[4-(5-fluoropyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E200    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[5-(trifluoromethyl)pyridin-3-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E201    2-[(1-{[4′-(2-hydroxypropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E202    2-({1-[(3′,5′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E203    2-({1-[(4′-fluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E204    2-({1-[(3′,5′-difluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E205    N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(3-pyridyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E206    N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(4-pyridyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E207    N-(2-methoxyethyl)-4-methyl-2-({1-[(2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide

From the 207 compounds, particular preference is given to the compoundshaving an EP2 receptor antagonism of >50 nM:

-   E2    2-{[1-(4-tert-butoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E3    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E5    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E7 2-{[1-(2-fluoro-4-methoxybenzo    yl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E8    2-{[1-(4-bromo-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E9    2-{[1-(2-fluoro-4-methylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E10    2-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E11    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E12    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E13    2-({1-[4-(4-chlorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E14    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4-methylphenoxy)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E15    2-({1-[4-(4-tert-butylphenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E16    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E17    N-(2-methoxyethyl)-2-({1-[4-(4-methoxyphenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E18    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E19    2-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E20    2-{[1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E21    2-{[1-(4-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E22    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E24    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphonyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E25    N-(2-methoxyethyl)-4-methyl-2-{1-[3-(trifluoromethyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E26    N-(2-methoxyethyl)-4-methyl-2-{[1-(3-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E27    2-{[1-(3-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E29    2-({1-[4-(cyclopentyloxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E30    2-({1-[4-(difluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E31    2-{[1-(4-cyanobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E36    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(1H-pyrazol-1-yl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E38    2-({1-[4-(difluoromethoxy)-2-fluorobenzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E39    2-({1-[2-fluoro-4-(pyrrolidin-1-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E40    2-({1-[(3,4′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E41    2-({1-[(3-fluoro-4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E44    2-[(1-{[3-fluoro-2′-(trifluoromethoxy)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E45    2-({1-[(2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E46    2-({1-[(2′,4′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E47    2-({1-[(2-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E48    N-(2-methoxyethyl)-4-methyl-2-({1-[(2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E51    2-({1-[2-fluoro-4-(morpholin-4-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E52    2-{[1-(4-bromobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E53    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E54    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E55    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E59    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide-   E60    N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]-methyl}-2H-indazole-5-carboxamide-   E61    N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}-methyl)-4-methyl-2H-indazole-5-carboxamide-   E62    N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E63    N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E64    2-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide-   E65    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-carboxamide-   E66    4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-N-[2-(2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-carboxamide-   E67    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxylethyl]-2H-indazole-5-carboxamide-   E68    4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-({1-[4-(trifluoromethyl)benzoyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E69    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide-   E70    2-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoro-ethoxy)ethyl]-2H-indazole-5-carboxamide-   E71    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E72    N-(2-isopropoxyethyl)-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E73    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E74    N-(2-isopropoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E75    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E76    2-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E77    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide-   E78    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoro-methoxy)ethyl]-2H-indazole-5-carboxamide-   E79    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide-   E80    4-methyl-N-[2-(trifluoromethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E81    N-(2-tert-butoxyethyl)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carboxamide-   E82    N-(2-tert-butoxyethyl)-2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E83    N-(2-tert-butoxyethyl)-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E84    N-(2-tert-butoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E85    2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-{2-[(2H3)methyloxy]-(2H4)ethyl}-2H-indazole-5-carboxamide-   E86    2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-{2-[(2H3)methyloxy](2H4)ethyl}-2H-indazole-5-carboxamide-   E87    2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E88    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide-   E89    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}-methyl)-2H-indazole-5-carboxamide-   E90    2-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E91    2-{[1-(4-chloro-2-fluorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E92    2-({1-[3-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E93    2-({1-[4-chloro-3-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E94    2-{[1-(4-cyclopropylbenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E95    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide-   E100    N-[2-(cyclopropyloxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide-   E101    N-[2-(cyclobutyloxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide-   E102    2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide-   E103    N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}-methyl)-4-methyl-2H-indazole-5-carboxamide-   E104    N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzoyl)azetidin-3-yl]-methyl}-2H-indazole-5-carboxamide-   E105    2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide-   E107    N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E108    2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E109    2-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E112    2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-carboxamide-   E113    4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide-   E114    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-azetidin-3-yl)methyl]-2H-indazole-5-carboxamide-   E115    2-({1-[4-(4-chlorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide-   E116    2-({1-[4-(4-chlorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E117    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)-azetidin-3-yl]methyl}-2H-indazole-5-carboxamide-   E125    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E126    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E127    4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E128    4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E131    2-({1-[4-(3-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide-   E132    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E137    2-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E138    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{[4′-(trifluoromethyl)biphenyl-4-yl]carbonyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E141    2-({1-[(4′-methoxy-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E143    2-({1-[(4′-fluoro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide-   E153    2-({1-[4-(4-cyanophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E154    2-{[1-(4-bromo-3-methylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E155    2-{[1-(4-tert-butylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E157    2-{[1-(4-cyclohexylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E160    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-3-yloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E161    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E162    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E163    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E164    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzoyl)-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E165    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide-   E166    2-({1-[(4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E168    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E170    2-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E171    2-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E172    2-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E173    N-(2-methoxyethyl)-4-methyl-2-[(1-{[4′-(trifluoromethyl)biphenyl-4-yl]carbonyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E174    2-({1-[4-(3-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E175    2-{[1-(2-fluoro-4-isopropoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E176    2-({1-[(3-fluoro-3′,4′-dimethylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E177    2-({1-[(2′,3-difluoro-4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E178    2-({1-[4-(difluoromethoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E179    2-({1-[4-(2-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E180    2-({1-[(4′-cyano-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E181    2-({1-[4-(5-chloropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E182    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E183    N-(2-methoxyethyl)-2-({1-[(4′-methoxy-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E184    2-({1-[(4′-chloro-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E185    2-[(1-{[4′-(2-cyanopropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E186    N-(2-methoxyethyl)-2-({1-[4-(5-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E187    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E188    N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E189    2-({1-[(4′-fluoro-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E190    N-(2-methoxyethyl)-4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide-   E191    N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide-   E193    2-({1-[(4′-fluoro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E194    2-({1-[(4′-chloro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E195    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E196    2-({1-[(4′-chloro-2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E197    2-({1-[(2′-chloro-4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E198    2-({1-[4-(5-chloropyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E199    2-({1-[4-(5-fluoropyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E200    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[5-(trifluoromethyl)pyridin-3-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E201    2-[(1-{[4′-(2-hydroxypropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E202    2-({1-[(3′,5′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide-   E203    2-({1-[(4′-fluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E204    2-({1-[(3′,5′-difluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide-   E205    N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(3-pyridyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E206    N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(4-pyridyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide-   E207    N-(2-methoxyethyl)-4-methyl-2-({1-[(2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide

Particular preference is furthermore given to the following compounds:

-   E16    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E126    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E161    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Administration of the EP2 receptor antagonist according to generalformula I or Ia can take place as a single dose or as two doses. Thedaily dose is 0.1-1000 mg, preferably 50-600 mg, where the dose may beadministered as a single dose to be administered once or divided into 2or more partial doses.

It may be necessary to deviate from the amounts mentioned of EP2receptor antagonist of the general formula I or Ia, depending on bodyweight, administration route, individual response to the activecompound, type of preparation and time or interval at whichadministration takes place. Thus, in some cases it may be sufficient touse less than the minimum amount mentioned above, whereas in other casesthe upper limit mentioned must be exceeded.

COX Inhibitors which, According to the Invention, are Contained in thePharmaceutical Composition

In principle, COX inhibitors suitable for use according to the inventionare all COX inhibitors available for other indications. This means bothselective and non-selective COX inhibitors. According to the invention,those suitable include:

-   C1 indomethacin;-   C2 diclofenac;-   C4 naproxen;-   C5 ibuprofen;-   C6 meloxicam;-   C7 piroxicam;-   C8 nimesulide;-   C9 ketoprofen;-   C10 tenoxicam;-   C11 mefanemic acid;-   C12 ketoralac;-   C13 celecoxib    (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulphonamide);-   C14 parecoxib    (N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulphonylpropionamide);-   C15 rofecoxib (4-(4-mesylphenyl)-3-phenylfuran-2(5H)-one);-   C16 valdecoxib    (4-[5-methyl-3-phenyl-4-isoxazoyl)benzenesulphonamide);-   C17 etoricoxib.

Particular preference is given to:

-   C1 indomethacin;-   C2 diclofenac;-   C4 naproxen;-   C5 ibuprofen;-   C6 meloxicam;-   C7 piroxicam;-   C8 nimesulide.

Very particular preference is given to:

-   C1 indomethacin;-   C2 diclofenac;-   C6 meloxicam;-   C7 piroxicam.

In the case of the COX inhibitors, too, administration of the COXinhibitors may be by administration of single doses or by administrationof two doses. In the case of the COX inhibitors, too, different dosagesare used, depending on the COX inhibitor employed. The amount of COXinhibitor present in the pharmaceutical composition varies, depending onthe chosen inhibitor. Dose ranges for the COX inhibitors used accordingto the invention result from the therapeutic doses per day for the COXinhibitor in question. These therapeutic doses refer to relativelylong-term treatments and continuous therapies, so that for the presentindication of on-demand contraception, it is also possible to use fourtimes the recommended therapeutic dose. The lower limit is considered tobe a quarter of the recommended therapeutic dose. In the case of the COXinhibitors, too, the dose can be administered as a single dose to beadministered once or divided into 2 or more partial doses.

According to the invention, the following dose ranges are suitable foron-demand use:

-   C1 indomethacin: 19-800 mg/day (daily therapeutic dose: 75-200    mg/day*)-   C2 diclofenac: 37.5-800 mg/day (daily therapeutic dose: 150-200    mg/day*)-   C4 naproxen: 125-4000 mg/day (daily therapeutic dose: 500-1000    mg/day*)-   C5 ibuprofen: 200-4800 mg/day (daily therapeutic dose: 800-1200    mg/day*)-   C6 meloxicam: 2-60 mg/day (daily therapeutic dose: 7.5-15 mg/day)-   C7 piroxicam: 5-80 mg/day (daily therapeutic dose: 20 mg/day*)-   C8 nimesulide: 25-800 mg/day (daily therapeutic dose: 100-200    mg/day*)-   C9 ketoprofen: 25-1200 mg/day (daily therapeutic dose: 100-300    mg/day*)-   C10 tenoxicam: 10-160 mg/day (daily therapeutic dose: 40 mg/day*)-   C11 mefanemic acid: 125-2000 mg/day (daily therapeutic dose: 500    mg/day*)-   C12 ketoralac: 2.5-160 mg/day (daily therapeutic dose: 10-40    mg/day*)-   C13 celecoxib: 25-800 mg/day (daily therapeutic dose: 100-200    mg/day*)-   C14 parecoxib: 12.5-200 mg/day (daily therapeutic dose: 50 mg/day*)-   C15 rofecoxib: 6-200 mg/day (daily therapeutic dose: 25-50 mg/day*)-   C16 valdecoxib: 10-160 mg/day (daily therapeutic dose: 40 mg/day)-   C17 etoricoxib: 15-360 mg/day (daily therapeutic dose: 60-90 mg/day)    *Huntjens et al. Rheumatology; (2005); 44:846-859

In the case of the COX inhibitors, too, it may, if required, benecessary to deviate from the above-mentioned amounts of COX inhibitors,namely depending on body weight, administration route, individualresponse to the reactive compound, type of preparation and time orinterval at which the administration takes place. Thus, in some cases itmay be sufficient to use less than the minimum amount mentioned above,whereas in other cases the upper limit mentioned must be exceeded.

The details given for the COX inhibitors refer to their combination withEP2 receptor antagonists according to the general formula I or Ia.

Combinations which are preferred in accordance with the inventioncomprise an EP2 receptor antagonist according to general formula Ia fromthe list

-   E16    N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E126    4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide-   E161    N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide    and a COX inhibitor from the list-   C1 indomethacin;-   C2 diclofenac;-   C4 naproxen;-   C5 ibuprofen;-   C6 meloxicam;-   C7 piroxicam;-   C8 nimesulide;    or COX inhibitors which are preferably used in accordance with the    invention, from the following list:-   C1 indomethacin;-   C2 diclofenac;-   C6 meloxicam;-   C7 piroxicam.

Use of the Pharmaceutical Composition for on-Demand Contraception andFertility Control

The invention furthermore provides the use of the pharmaceuticalcomposition comprising at least one EP2 receptor antagonist of formulaIa and at least one COX inhibitor for on-demand contraception and forfertility control.

On-demand contraception, fertility control on demand, precoitalcontraception or contraception on demand all refer to the on-demand useof one or more substances for preventing unwanted pregnancy. Theadministration can be before or shortly after expected sexualintercourse. Here, on-demand does not mean optional. Rather, thesubstance/substances has/have to be administered to prevent unwantedpregnancy.

Contraception, birth control or fertility control all refer likewise tothe continuous regular intake of one or more substances at low dosageaccording to a fixed protocol over a relatively long period of timeextending over a plurality of cycles. Intake of the pharmacologicalcontraceptive is independent of the frequency and time of sexualintercourse.

Administration Route

The pharmaceutical compositions according to the invention and their usecan be systematic and/or local. To this end, they can be administered ina suitable manner, for example orally, pulmonarily, nasally, dermally ortransdermally. Further administration routes are vaginal orintrauterine. Suitable for vaginal administration are tampons, gels,suppositories, pessaries or intravaginal rings. Suitable forintrauterine administration are, inter alia, intrauterine systems orintrauterine pessaries.

Suitable for oral administration are administration forms described inthe prior art as being suitable and comprising the EP2 receptorantagonists according to general formula I or Ia according to theinvention and COX inhibitors in crystalline and/or amorphized and/ordissolved form, such as tablets (uncoated tablets or coated tablets, forexample with enteric coatings or coatings which dissolve in a delayedmanner or insoluble coatings controlling the release of the compoundaccording to the invention), tablets which rapidly disintegrate in theoral cavity or films/wafers, films/lyophilizates, capsules (for examplehard or soft gelatine capsules), sugar-coated tablets, wafers, granules,pellets, powders, emulsions, suspensions, aerosols or solutions.

Use is also possible in liquid form, such as for example as syrup, towhich a sweetener is optionally added. Likewise, for the oral use ofsuch compounds, the clathrates thereof are also suitable, for examplethe clathrates with alpha, beta or gamma cyclodextrin or elsebeta-hydroxypropyl cyclodextrin may be mentioned.

Suitable for the other administration routes are, for example,inhalative medicinal forms (inter alia powder inhalers, nebulizers),nasal drops, solutions, sprays; tablets, films/wafers or capsules to beadministered lingually, sublingually or buccally, suppositories, aqueoussuspensions (lotions, shake mixtures), lipophilic suspensions,ointments, creams, transdermal systems (for example patches), milk,pastes, foams or powders for sprinkling.

The pharmaceutical compositions according to the invention can beconverted into the stated administration forms. This can take place in amanner known per se by mixing with inert non-toxic pharmaceuticallysuitable auxiliaries. These auxiliaries include, inter alia, carriers(for example microcrystalline cellulose, lactose, mannitol), solvents(for example liquid polyethylene glycols), emulsifiers and dispersantsor wetting agents (for example sodium dodecylsulphate, polyoxysorbitaneoleate), binders (for example polyvinylpyrrolidone), synthetic andnatural polymers (for example albumin), stabilizers (for exampleantioxidants such as, for example, ascorbic acid), colorants (forexample inorganic pigments such as iron oxides) and taste and/or odourcorrigents.

They optionally contain additives, which are for example intended tofunction as fillers, binders, disintegrants, lubricants, solvents,solution mediators, masking flavours, colorant, or emulsifiers. Types ofadditive in the sense of the invention are for example saccharides(mono-, di-, tri-, oligo-, and/or polysaccharides), fats, waxes, oils,hydrocarbons, anionic, nonionic, cationic, natural, synthetic orsemisynthetic surfactants. In addition, they optionally containadditives such as preservatives, stabilizers, wetting agents oremulsifiers; salts for alteration of the osmotic pressure or buffers.

The present invention furthermore provides medicaments or pharmaceuticalcompositions comprising at least one EP2 receptor antagonist accordingto general formula I or Ia according to the invention and at least oneCOX inhibitor, usually together with one or more inert non-toxicpharmaceutically suitable auxiliaries, and their use for on-demandcontraception and fertility control.

The pharmaceutical formulation may comprise at least one EP2 receptorantagonist of the general formula I or Ia and at least one COXinhibitor, either together in one administration form (for example acombination tablet) or in two separate administration forms (for examplea tablet), where one administration form comprises at least one EP2receptor antagonist and the other administration form comprises at leastone COX inhibitor.

The person skilled in the art is familiar with how to prepare thepharmaceutical formulation. The preparation of a formulation ascombination tablet is described in preparation example 1.

Administration Protocol

The invention furthermore provides an administration protocol foron-demand contraception where a pharmaceutical composition comprising atleast one COX inhibitor from the list mentioned above and at least oneEP2 receptor antagonist according to general formula I or Ia areadministered in a single administration dose over a period of up to 24hours, preferably 6-12 hours, prior to expected sexual intercourse or ofup to 2 hours after sexual intercourse.

In an alternative embodiment, the single dose preparation may also betaken up to at most 24 hours after sexual intercourse.

Also provided is an administration protocol where two separatepharmaceutical compositions each comprising at least one COX inhibitorfrom the list mentioned above and at least one EP2 receptor antagonistof the general formula I or Ia are administered in succession, at aninterval. The compositions of the two pharmaceutical compositions can beidentical or different with respect to selection and dosage of the EP2receptor antagonist of the general formula I or Ia and the COXinhibitor. Administration of the first pharmaceutical composition iswithin a period of up to 24 hours, preferably 6-12 hours, prior toexpected sexual intercourse, and administration of the secondpharmaceutical composition is within a period of up to 48 hours afterthe expected sexual intercourse.

In the cases where the two pharmaceutical compositions are different,the dose of one of the active compounds or of both active compounds ofthe pharmaceutical composition taken prior to sexual intercourse may belower than that for the pharmaceutical composition taken after sexualintercourse.

By an appropriate administration protocol, it is possible to achievesufficiently high active compound plasma levels for a sufficiently longperiod of time to counteract unwanted pregnancy. Thus, in the femalegenital tract sperms are viable for about 5 days. If appropriate,administration after sexual intercourse may also take place as aplurality of doses to achieve active plasma concentrations over a periodof up to 5 days.

Furthermore, by administering two pharmaceutical compositions it ispossible to achieve an even better efficacy of the preparation. Also, incases where the expected sexual intercourse has not taken place, theactive compound load can be reduced by dispensing with theadministration which should have taken place after the expected sexualintercourse.

The invention furthermore provides a kit for on-demand contraception,comprising at least two tablets each comprising at least one COXinhibitor and at least one EP2 receptor antagonist of the generalformula I or Ia. A first tablet is taken during a period of up to 24hours, preferably 6-12 hours, prior to the expected sexual intercourse,and at least one further tablet is taken during a period of up to 48hours after the expected sexual intercourse.

According to the invention, the kit may comprise the two tablets up to 5times to allow on-demand contraception of 5 expected sexual intercoursesat intervals of at least 24 hours.

Process for the Production of the Compounds According to the Inventionof the General Formula I and Ia:

The following description of the production process is already containedin patent application PCT/EP2012/073556, unpublished at the prioritydate of the present specification.

For this, for example a carboxylic acid of the formula VIII is reactedwith an amine of the general formula XI by methods known to thoseskilled in the art to give the compounds according to the invention ofthe general formula I (Scheme 1).

The reaction takes place in that for example a carboxylic acid of theformula VIII is converted with isobutyl chloroformate in the presence ofa tertiary amine, for example triethylamine, into a mixed anhydride,which reacts with an alkali metal salt of the appropriate amine XI in aninert solvent or solvent mixture, for example tetrahydrofuran,N,N-dimethylformamide or dimethoxyethane at temperatures between −30° C.and +60° C. to give the target compounds of the formula I.

It is also possible to activate a carboxylic acid VIII with reagentssuch as for example dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI),N-hydroxybenzotriazole (HOBT) orN-[(dimethylamino)-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methyliden]-N-methylmethanaminiumhexafluorophosphate (HATU). For example the reaction with HATU takesplace in an inert solvent, for example N,N-dimethylformamide or dimethylsulphoxide in the presence of the appropriate amine XI and a tertiaryamine, for example triethylamine or diisopropylamine, at temperaturesbetween −30° C. and +60° C.

It is also possible, to convert a carboxylic acid of the formula VIIIinto the corresponding carboxylic acid chloride with an inorganic acidchloride, for example phosphorus pentachloride, phosphorus trichlorideor thionyl chloride and then into the target compounds of the generalformula I in pyridine or an inert solvent, such as for exampleN,N-dimethylformamide, in the presence of the appropriate amine XI and atertiary amine, for example triethylamine, at temperatures between −30°C. and +60° C.

The compounds according to the invention of the general formula I canalso be obtained from bromoindazoles of the general formula VI underpalladium(O) catalysis by reaction with an appropriate amine XI andcarbon monoxide (CO) or a carbon monoxide source, such as for examplemolybdenum hexacarbonyl in a suitable solvent or solvent mixture, forexample 1,4-dioxan/water or tetrahydrofuran, addition of a base such asfor example sodium carbonate or 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)and a catalyst-ligand mixture, for example palladium(II) acetate ortransbis(acetato)bis[o-(di-o-tolylphosphino)benzyl]-dipalladium(II)/tri-tert-butylphosphinotetrafluoroborateat temperatures between 80° C. and 160° C. (optionally with microwaveirradiation between 80-200 watts), and in case of the use of carbonmonoxide at a CO pressure of 5-15 bar (Scheme 1).

The compounds according to the invention of the general formula I canalso be obtained from amines of the general formula XV by reaction withcarboxylic acids (Y═OH), chlorides (Y═Cl) or anhydrides (e.g.Y═O—C(O)—O—CH₂(CH)₃CH₃) of the formula IX in the manner described forthe production of the compounds I from the compounds VIII and XI (Scheme2).

Likewise, the compounds of the general formula I can be obtained fromcompounds of the general formula XVI, wherein LG′ for example means Bror I, by reaction with compounds of the formula XVIII (Scheme 2).

Compounds of the formula XVIII are for example (Het)Arylboronic acids(R³-Met=(Het)Ar—B(OH)₂) or boronic acid pinacol esters(R³-Met=(Het)Ar—BPin), which are converted to biaryl compounds of theformula I by methods known to those skilled in the art in a suitablesolvent, for example N,N-dimethylformamide, tetrahydrofuran,dimethoxyethane and optionally water and addition of a base, for exampletriethylamine, potassium carbonate, caesium carbonate and acatalyst-ligand mixture, for example of palladium(II)acetate/triphenylphosphine,bis(diphenylphosphino)ferrocenedichloropalladium (II)(/1,1′-bis(diphenylphosphino)ferrocene/Cu(I)Cl) at temperatures between20° C. and 120° C.

Compounds of the formula XVIII can also be (Het)Arylalcohols(R³-Met=(Het)ArO—H), which are converted into biaryl ethers of theformula I by methods known to those skilled in the art in a suitablesolvent, for example N,N-dimethylformamide or dimethyl sulphoxide withaddition of a base, for example potassium carbonate, caesium carbonateunder copper-(I) catalysis e.g. with copper(I) bromide at temperaturesbetween 60° C. and 120° C.

The carboxylic acids of the general formula VIII can for example beobtained from esters of the formula VII by ester saponification in asuitable solvent or solvent mixture, for example methanol, ethanol ortetrahydrofuran, water with addition of an aqueous solution of an alkalimetal hydroxide, for example sodium hydroxide or lithium hydroxide attemperatures between 20° C. and 60° C. (Scheme 1).

In the same manner, the carboxylic acids XIII can be obtained from theesters XII (Scheme 2, PG: e.g. Boc (tert-butyloxycarbonyl) and thecarboxylic acids XXI from the esters XX (Scheme 3, LG′: e.g. Br or I).

The esters of the general formula VII can be obtained frombromoindazoles of the general formula VI under palladium(O) catalysis byreaction with carbon monoxide or a carbon monoxide source, such as forexample molybdenum hexacarbonyl, and methanol in a suitable solvent, forexample dimethyl sulphoxide, N,N-dimethylformamide or tetrahydrofuranand addition of a base, for example triethylamine or1,8-diazabicyclo(5.4.0)undec-7-ene and a catalyst-ligand mixture, forexample of palladium(II) acetate/bis-1,3-diphenylphosphinopropane ortrans bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)/tri-tert-butylphosphinotetrafluoroborateat temperatures between 20° C. and 140° C. (optionally with microwaveirradiation between 80-200 watts), and in case of the use of carbonmonoxide at a CO pressure of 5-15 bar (Scheme 1).

This method is not restricted to methyl esters, i.e. to the use ofmethanol, but can also be extended to other esters. Thus for example byuse of ethanol instead of methanol in this manner, the correspondingethyl esters can be synthesized.

In the same manner, the esters XII can be obtained from the bromides IV(Scheme 2, -PG: e.g. -Boc).

The amides of the general formula VII can also be obtained from theamines of the general formula XIX by reaction with compounds of thegeneral formula IX (Scheme 3), analogously to the synthesis of thecompounds I from the compounds XV (Scheme 2).

The compounds of the general formula VII can also be obtained fromcompounds of the formula XX and reaction with compounds of the formulaXVIII (Scheme 3), analogously to the described conversion of thecompounds XVI to the compounds of the formula I (Scheme 2).

The amides of the general formula VI can be obtained from amines of thegeneral formula V by reaction with carboxylic acids (Y═OH), chlorides(Y═Cl) or anhydrides (e.g. Y═0-C(O)—O—CH₂(CH)₃CH₃) of the formula IX(Scheme 1), as described for the conversion of amines XV to amides I(Scheme 2).

The amides of the general formula XVI can be obtained in analogousmanner from amines XV and carboxylic acids or carboxylic acidderivatives XVII (Y: e.g. OH, Cl or O—C(O)—O—CH₂(CH)₃CH₃; LG′: e.g. Bror I) (Scheme 2).

Analogously, amines XX (LG′: e.g. Br or I) can be obtained from aminesXIX and carboxylic acids or carboxylic acid derivatives XVII (Y: e.g.OH, Cl or O—C(O)—O—CH₂(CH)₃CH₃; LG′: e.g. Br or I) (Scheme 3).

Likewise, carboxylic acids XIII (PG: e.g. Boc) can be converted withamines XI to amides XIV (Scheme 2) and carboxylic acids XXI (LG′: e.g.Br, I) with amines XI to amides XVI (Scheme 3) in this manner.

The secondary amines V can be obtained from the corresponding carbamatesIV (PG: e.g. Boc) by methods known to those skilled in the art (Scheme1).

Thus for example tert-butyl carbamates can be converted into the aminesV in an acidic medium with the use of e.g. trifluoroacetic acid orhydrochloric acid in a suitable solvent or solvent mixture such as forexample dichloromethane, dioxan or acetone/water. In an anhydrous mediumthe amines V are formed as the corresponding salts.

Analogously, the amines XV can be obtained from the carbamates XIV(Scheme 2) and the amines XIX from the carbamates XII (Scheme 3).

The 2H-indazoles of the general formulae IV and VI can be produced invarious ways.

For example, 2H-indazoles IV can be obtained from 1H-indazoles of thegeneral formula II by alkylation with compounds of the general formulaIII (PG: e.g. Boc, LG: e.g. Br, I, O-Ts (tosyloxy) or O-Ms (mesyloxy))in a suitable solvent, for example N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulphoxide or else THF, 1,4-dioxan andaddition of a base such as for example potassium carbonate or caesiumcarbonate (optionally with addition of tetrabutylammonium iodide) orelse sodium bis(trimethylsilyl)amide, at temperatures between 25° C. and100° C. or else in case of the use of sodium bis(trimethylsilyl)amide 0°C. and 25° C. (Scheme 1).

Analogously the 2H-indazoles of the general formula VI can be obtainedfrom 1H-indazoles of the general formula II and compounds of the generalformula X (LG: e.g. Br, I, O-Ts or O-Ms) (Scheme 1).

The 2H-indazoles of the general formula IV can also be obtained fromortho-nitrobenzaldehydes of the general formula XXVII by reaction withan appropriate amine XXVIII (PG: e.g. Boc) in a suitable solvent, forexample 1,4-dioxan and addition of a reducing agent such as for exampletriethyl phosphite, possibly with addition of potassium carbonate orcaesium carbonate or powdered molecular sieve, at temperatures between100° C. and 160° C. (Scheme 4).

Analogously, the 2H-indazoles of the general formula VI can be obtainedfrom ortho-nitrobenzaldehydes XXVII by reaction with amines XXIX (Scheme4).

The compounds of the general formula XIV (PG: e.g. Boc) can also beobtained from bromoindazoles of the general formula IV (PG: e.g. Boc)under palladium(O) catalysis by reaction with an appropriate amine XIand carbon monoxide or a carbon monoxide source, such as for examplemolybdenum hexacarbonyl (Scheme 2), analogously to the described processfor the conversion of the bromoindazoles VI to the compounds of thegeneral formula I, (Scheme 1).

The ortho-nitrobenzaldehydes of the general formula XXVII can beproduced from the ortho-nitrotoluenes of the general formula XXVI bymethods known to those skilled in the art in two reaction steps (Scheme4).

For this, an ortho-nitrotoluene XXVI is dissolved in a suitable solventsuch as N,N-dimethylformamide and converted with N,N-dimethylformamidedimethyl acetal at temperatures of 100-140° C. to the correspondingenamine, which is immediately oxidized at temperatures of 0° C.-20° C.to the corresponding ortho-nitrobenzaldehyde with a suitable oxidizingagent such as for example NaIO₄ in a suitable aqueous solvent mixturesuch as water/N,N-dimethylformamide and optionally with addition of abase such as for example triethylamine, N,N-diisopropylethylamine,sodium hydrogen carbonate or sodium carbonate.

The ortho-nitrotoluenes of the general formula XXVI can be produced fromthe ortho-methylanilines of the general formula XXV by methods known tothose skilled in the art (Scheme 4).

For this, an ortho-methylaniline XXV is dissolved in a suitable solventsuch as dichloromethane or chloroform, treated with zirconium(IV)tert-butoxide, ground molecular sieve 3 Å and tert-butyl hydroperoxideand reacted at temperatures of 20-40° C.

The 1H-indazoles of the general formula II can be liberated from theacetamides of the general formula XXIV by methods known to those skilledin the art (Scheme 4).

For this, for example an acetamide XXIV is reacted in a suitable solventsuch as methanol or ethanol and addition of 37% hydrochloric acid attemperatures of 40-80° C.

Analogously thereto, the anilines of the formula XXV can be liberatedfrom the acetanilides of the formula XXIII (Scheme 4).

The acetamides of the general formula XXIV can be produced from theortho-methyl-acetanilides of the general formula XXIII by methods knownto those skilled in the art (Scheme 4).

For this, the ortho-methyl-acetanilides XXIII are dissolved in asuitable solvent such as chloroform or toluene, treated with aceticanhydride, isopentyl or tert-butyl nitrite, and optionally potassiumacetate and 18-crown-6, and reacted at temperatures of 60-100° C.

The ortho-methyl-acetanilides XXIII can be produced from theacetanilides of the general formula XXII by bromination by methods knownto those skilled in the art (Scheme 4).

For this, the acetanilides XXII, which can for example be obtained fromthe corresponding anilines by reaction with acetic anhydride in asuitable solvent (e.g. toluene) at temperatures of 80-110° C., isreacted with bromine in glacial acetic acid at temperatures of 10-25° C.

The compounds of the general formula III wherein LG means —OTs or —OMscan be produced by methods known to those skilled in the art from thecorresponding alcohols.

For this, the alcohols are reacted with p-toluenesulphonyl chloride ormethanesulphonyl chloride at temperatures between 0° C. and 40° C. in asuitable solvent, e.g. dichloromethane or tetrahydrofuran or toluene andaddition of a suitable base, e.g. pyridine or triethylamine.

The compounds of the general formula X, wherein LG means —OTs or —OMs,can be produced from the corresponding amino alcohols XXX by methodsknown to those skilled in the art (Scheme 4).

For this, in a first step the amino alcohols XXX are converted to thecorresponding amides XXXI in a suitable solvent, e.g. dichloromethane,with arylcarboxylic acid chlorides of the formula Cl—C(O)—Ar—R³ andaddition of a suitable base, e.g. triethylamine, at temperatures between0° C. and 25° C. Optionally, corresponding esters formed as by-productscan be separated or else saponified to the corresponding alcohols XXXIunder standard conditions, e.g. with use of a base, e.g. potassiumhydroxide, in a suitable solvent mixture, e.g. ethanol/water, attemperatures between 20° C. and 40° C.

The N-protected alcohols XXXI thus obtained can be converted into thecompounds of the formula X with LG: —OTs or —OMs analogously to theprocess described for the synthesis of the compounds III. Compounds ofthe formula X with LG: —Br can be obtained from the correspondingalcohols XXXI by methods known to those skilled in the art by reactionwith a brominating agent such as for example CBr₄ with addition of PPh₃as an oxophile in a suitable solvent, e.g. chloroform, at temperaturesbetween 20° C. and 40° C.

The compounds of the general formula XXIX, can be produced by methodsknown to those skilled in the art for example from the amines of theformula XXXII (Scheme 4).

For this, in a first step, the amines XXXII are converted to thecorresponding amides XXXIII analogously to the synthesis of thecompounds I from the compounds XV.

The tert-butyloxycarbonyl group in compounds of the formula XXXIII iscleaved analogously to the conversion of the compounds IV to thecompounds V, hence the compounds of the formula XXIX can be obtained.

Production of the Compounds According to the Invention:

The following description of the production of the compounds accordingto the invention is already contained in patent applicationPCT/EP2012/073556, unpublished at the priority date of the presentspecification.

The following examples illustrate the production of the compoundsaccording to the invention of the general formula (I) and Ia, withoutlimiting the range of the claimed compounds to these examples.

The compounds according to the invention of the general formula (I) canbe produced and characterized as described below.

LC-MS: Waters Acquity HPLC/MS 100-800 Daltons; 20 V (Micromass/Waters ZQ4000); Column: BEHC 18 (Waters), 2.1×50 mm, BEH 1.7 μm; Mobile phase: A:H₂O/0.05% HCOOH, B: CH₃CN/0.05% HCOOH. Gradient: 10-90% B in 1.7 min,90% B for 0.2 min, 98-2% B in 0.6 min; Flow rate: 1.3 ml/min, Detection:UV=200-400 nm.

Chiral HPLC Separation Method A:

Preparative chiral HPLC: System: Dionex: Pump P 580, Gilson: LiquidHandler 215, Knauer: UV detector K-2501 Column: Chiralpak AD-H 5 μm250×20 mm; Solvent: hexane/ethanol 50:50; Flow rate: 15 ml/min;injection volume: 0.5 ml; Detection: UV 254 nm.

Analytical chiral HPLC: System: Waters: Alliance 2695, DAD 996, ESA:Corona; Column: Chiralpak AD-H 5 μm 150×4.6 mm Solvent: hexane/ethanol50:50; Flow rate: 1.0 ml/min; Temperature: 25° C.; injection: 5 μl;Detection: DAD 254 nm.

Chiral HPLC Separation Method B:

Preparative chiral HPLC: System: Dionex: Pump P 580, Gilson: LiquidHandler 215, Knauer: UV detector K-2501 Column: Chiralpak IC 5 μm 250×30mm; Solvent: ethanol/methanol 50:50; Flow rate: 30 ml/min; injectionvolume: 0.5 ml; Detection: UV 254 nm.

Analytical chiral HPLC: System: Waters: Alliance 2695, DAD 996, ESA:Corona; Column: Chiralpak IC 5 μm 150×4.6 mm Solvent: ethanol/methanol50:50; Flow rate: 1.0 ml/min; Temperature: 25° C.; injection: 5 μl;Detection: DAD 254 nm.

Chiral HPLC Separation Method C:

Preparative chiral HPLC: System: Dionex: Pump P 580, Gilson: LiquidHandler 215, Knauer: UV detector K-2501 Column: Chiralpak AD-H 5 μm250×20 mm; Solvent: hexane/2-propanol 50:50; Flow rate: 15 ml/min;injection volume: 0.25 ml; Detection: UV 254 nm.

Analytical chiral HPLC: System: Waters: Alliance 2695, DAD 996, ESA:Corona; Column: Chiralpak AD-H 5 μm 150×4.6 mm Solvent:hexane/2-propanol 50:50; Flow rate: 1.0 ml/min; Temperature: 25° C.;injection: 5 μl; Detection: DAD 254 nm.

Chiral HPLC Separation Method D:

Preparative chiral HPLC: System: Dionex: Pump P 580, Gilson: LiquidHandler 215, Knauer: UV detector K-2501 Column: Chiralpak IB 5 μm 250×20mm; Solvent: hexane/ethanol 70:30; Flow rate: 20 ml/min; injectionvolume: 0.1 ml; Detection: UV 210 nm.

Analytical chiral HPLC: System: Waters: Alliance 2695, DAD 996, ESA:Corona; Column: Chiralpak IB 5 μm 150×4.6 mm Solvent: hexane/ethanol70:30; Flow rate: 1.0 ml/min; Temperature: 25° C.; injection: 5 μl;Detection: DAD 230 nm.

Chiral HPLC Separation Method E:

Preparative chiral HPLC: System: Dionex: Pump P 580, Gilson: LiquidHandler 215, Knauer: UV detector K-2501 Column: Chiralpak IC 5 μm 250×20mm; Solvent: ethanol/methanol 50:50; Flow rate: 15 ml/min; injectionvolume: 0.3 ml; Detection: UV 230 nm.

Analytical chiral HPLC: System: Waters: Alliance 2695, DAD 996, ESA:Corona; Column: Chiralpak IC 5 μm 150×4.6 mm Solvent: ethanol/methanol50:50; Flow rate: 1.0 ml/min; Temperature: 25° C.; injection: 5 μl;Detection: DAD 230 nm.

Abbreviations

-   Boc tert-butoxycarbonyl-   CO carbon monoxide-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCM dichloromethane-   DMF N,N-dimethylformamide-   DMSO dimethyl sulphoxide-   ESI; ES+ electrospray ionization (in MS); positive charged ion trace-   hr(s) hour(s)-   HATU    N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylen]-N-methylmethanaminium    hexafluorophosphate N-oxide-   HPLC high pressure, high performance liquid chromatography-   conc. concentrated-   LC-MS liquid chromatography-coupled mass spectroscopy-   M molar-   min(s) minute(s)-   MS mass spectroscopy-   N normal-   NMR nuclear resonance spectroscopy-   R_(t) retention time (in HPLC and LC)-   RT room temperature-   tert tertiary-   THF tetrahydrofuran

Example 12-{[1-(4-cyano-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

To a solution of 33.7 mg of 4-cyano-2-fluorobenzoic acid in 1.0 mldimethyl sulphoxide were added 85.5 mg of HATU, 75 mg of the amineprepared in Example 1a and 0.071 ml of N,N-diisopropylethylamine andthis was stirred for 1 hour at 25° C. The mixture was concentrated invacuo and the residue thus obtained purified by HPLC. Yield: 43.3 mg ofthe title compound.

¹H-NMR (400 MHz, DMSO-d₆): □ [ppm], 1.07-1.28 (2H), 1.30-1.44 (1H),1.47-1.61 (1H), 2.18-2.34 (1H), 2.49 (3H), 2.71-2.83 (1H), 2.92-3.08(1H), 3.32 (4H), 3.36 (2H), 3.42 (2H), 4.31 (2H), 4.39-4.51 (1H), 7.14(1H), 7.38 (1H), 7.50-7.63 (1H), 7.71-7.79 (1H), 7.95 (1H), 8.09-8.15(1H), 8.47 (1H).

The starting material for the above title compound was prepared asfollows:

Example 1aN-(2-methoxyethyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamidehydrochloride

To 855.1 mg of 1b were added 4.5 ml of 4M hydrochloric acid in dioxanand 1 ml dioxan. An oily mass was formed, which dissolved on vigorousstirring and gentle warming. The mixture was stirred for 1 hr at ca. 30°C. The reaction mixture was concentrated. Yield: 764.7 mg of the titlecompound, which was further reacted without further purification.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=1.33-1.50 (2H), 1.52-1.62 (2H),2.17-2.31 (1H), 2.32-2.38 (1H), 2.49 (3H), 2.67-2.86 (2H), 3.13-3.28(5H), 3.31-3.46 (4H), 4.33 (2H), 7.16 (1H), 7.38 (1H), 8.13 (1H), 8.53(1H), 8.71-8.88 (1H), 8.99-9.11 (1H).

Example 1b Tert-butyl4-({5-[N-(2-methoxyethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)piperidin-1-carboxylate

Version A: 2820 mg of 1c, 1556 mg of 2-methoxyethylamine, 1823 mg ofmolybdenum hexacarbonyl, 200.4 mg of tri-tert-butylphosphinetetrafluoroborate and 647.5 mg oftrans-bis(acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)were placed in portions in three microwave tubes and suspended with 56ml THF. Then 3.1 ml of DBU were added and the mixtures stirred for 20mins at 125° C. and 200 watts in the microwave. The reaction mixtureswere combined, filtered and diluted with some ethyl acetate and theorganic phase washed twice with water and once with saturated sodiumchloride solution. This was dried over sodium sulphate, filtered andconcentrated. The residue was chromatographed on the Biotage SP4.Gradient: ethyl acetate/methanol 0-10%. Yield: 885.1 mg of the titlecompound.

Version B: 780 mg of 1 d and 1747 mg of HATU were first dissolved in 10ml DMSO. Next, 314 mg of 2-methoxyethylamine and 1080 mg ofN,N-diisopropylethylamine were added. The mixture was stirred for 1 hrat RT. The reaction mixture was poured into water and extracted threetimes with ethyl acetate. The combined organic phases were washed withsaturated sodium chloride solution, dried over sodium sulphate, filteredand concentrated. The residue was purified chromatographically on theBiotage SP4. Gradient: ethyl acetate/methanol 0-10%. Yield: 740 mg ofthe title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.01-1.13 (2H), 1.34 (9H), 1.36-1.43(2H), 2.06-2.19 (1H), 2.49 (3H), 2.59-2.70 (2H), 3.29 (3H), 3.33-3.39(2H), 3.40-3.45 (2H), 3.82-3.93 (2H), 4.28 (2H), 7.14 (1H), 7.38 (1H),8.09-8.14 (1H), 8.46 (1H).

Example 1c Tert-butyl4-[(5-bromo-4-methyl-2H-indazol-2-yl)methyl]piperidin-1-carboxylate

5 g of 5-bromo-4-methyl-1H-indazole was dissolved in 110 ml DMF andtreated with 11.5 g of caesium carbonate and 7.9 g ofN-Boc-4-(bromomethyl)piperidine. The mixture was stirred for 3 hrs at60° C. and overnight at RT. The reaction mixture was next diluted withethyl acetate, and the organic phase was washed twice with water, driedover sodium sulphate, filtered and concentrated. The residue waspurified chromatographically on the Biotage SP4 via a 65i-Si column.Gradient: hexane/ethyl acetate 0-100%. Yield: 3.53 g of the titlecompound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.99-1.12 (2H), 1.34 (9H), 1.36-1.44(2H), 2.04-2.19 (1H), 2.47 (3H), 2.54-2.72 (2H), 3.82-3.93 (2H), 4.27(2H), 7.29 (1H), 7.34 (1H), 8.46 (1H).

Example 1d2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-4-methyl-2H-indazol-5-carboxylicacid

1080 mg of 1e were dissolved in 8 ml methanol and treated with 1235 mgof lithium hydroxide in 10 ml water. A further 2 ml THF were added assolubilizer. The mixture was stirred for 24 hrs at RT. Next the methanoland THF were distilled off. The aqueous residue was diluted with waterand washed once with ethyl acetate. The aqueous phase was acidified with10% sulphuric acid and extracted twice with ethyl acetate. The combinedorganic phases were dried over sodium sulphate, filtered andconcentrated. Yield: 880 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.99-1.18 (2H), 1.37-1.48 (2H), 1.34(9H), 2.05-2.21 (1H), 2.53-2.70 (2H), 2.73 (3H), 3.81-3.94 (2H), 4.29(2H), 7.39 (1H), 7.62 (1H), 8.62 (1H), 11.92-12.31 (1H).

Example 1e Methyl2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl)}-4-methyl-2H-indazol-5-carboxylate

666 mg of 1c, 156.8 mg of methanol, 645.8 mg of molybdenum hexacarbonyl,47.3 mg of tri-tert-butylphosphine tetrafluoroborate and 123.5 mg oftrans-bis(acetato)-bis[o-(di-o-tolyl-phosphino)benzyl]dipalladium(II)were placed in a microwave tube and suspended in 15 ml THF. Then 0.7 mlof DBU were added and the mixture was stirred for 20 mins at 125° C. and150 watts in the microwave. Next, it was concentrated, taken up in ethylacetate and the organic phase washed twice with water and once withsaturated sodium chloride solution. It was dried over sodium sulphate,filtered and concentrated. The residue was chromatographed on theBiotage SP4. Gradient: hexane/ethyl acetate 0-100%. Yield: 363 mg of thetitle compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.01-1.12 (2H), 1.34 (9H), 1.37-1.45(2H), 2.08-2.19 (1H), 2.53-2.69 (2H), 2.73 (3H), 3.79 (3H), 3.83-3.93(2H), 4.30 (2H), 7.42 (1H), 7.62 (1H), 8.67 (1H).

Example 22-({1-[4-tert-(butoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 35.9 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 1a and 39.7 mg of4-(tert-butoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.09-1.26 (2H), 1.29 (9H), 1.35-1.58(2H), 2.15-2.35 (1H), 2.49 (3H), 2.69-2.97 (2H), 3.24 (3H), 3.32-3.47(4H), 4.23-4.40 (2H), 6.98 (2H), 7.14 (1H), 7.23 (2H), 7.38 (1H), 8.10(1H), 8.47 (1H).

Example 32-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 51.6 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 1a and 47.5 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.10-1.30 (2H), 1.32-1.58 (2H),2.19-2.35 (1H), 2.49 (3H), 2.71-3.02 (2H), 3.25 (3H), 3.32-3.39 (2H),3.40-3.47 (2H), 4.32 (2H), 6.95 (2H), 7.06-7.14 (3H), 7.15-7.27 (3H),7.31-7.42 (3H), 8.07-8.15 (1H), 8.47 (1H).

Example 4N-(2-methoxyethyl)-4-methyl-2-{[1-(4-morpholinobenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 48.1 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 1a and 42.3 mg of4-morpholinobenzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.09-1.29 (2H), 1.36-1.53 (2H),2.16-2.34 (1H), 2.49 (3H), 2.72-2.94 (2H), 3.13 (4H), 3.24 (3H), 3.42(4H), 3.64-3.75 (4H), 3.92-4.15 (1H), 4.32 (2H), 6.92 (2H), 7.14 (1H),7.20 (2H), 7.38 (1H), 8.07-8.15 (1H), 8.47 (1H).

Example 52-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 50.1 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 1a and 44.2 mg of4-(4-fluorophenyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.11-1.32 (2H), 1.32-1.64 (2H),2.20-2.36 (1H), 2.49 (3H), 2.63-3.08 (2H), 3.24 (3H), 3.42 (4H),3.50-3.73 (1H), 4.24-4.55 (3H), 7.10-7.20 (1H), 7.27 2H), 7.41 (3H),7.67 (4H), 8.03-8.16 (1H), 8.48 (1H).

Example 62-{[1-(2-fluoro-4-mesylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 40.1 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 1a and 44.6 mg of2-fluoro-4-mesylbenzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.06-1.30 (2H), 1.31-1.45 (1H),1.51-1.64 (1H), 2.20-2.37 (1H), 2.49 (3H), 2.71-2.85 (1H), 2.91-3.10(1H), 3.24 (3H), 3.26 (3H), 3.33-3.39 (2H), 3.42 (2H), 4.24-4.39 (2H),4.40-4.51 (1H), 7.14 (1H), 7.38 (1H), 7.59-7.69 (1H), 7.76-7.89 (2H),8.07-8.14 (1H), 8.47 (1H).

Example 72-{[1-(2-fluoro-4-methoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 43.1 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 1a and 34.8 mg of2-fluoro-4-methoxybenzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.05-1.25 (2H), 1.32-1.44 (1H),1.48-1.61 (1H), 2.18-2.33 (1H), 2.49 (3H), 2.63-2.79 (1H), 2.88-3.05(1H), 3.24 (3H), 3.42 (d, 5H), 3.75 (3H), 4.27-4.35 (2H), 4.37-4.49(1H), 6.77-6.89 (2H), 7.14 (1H), 7.24 (1H), 7.38 (1H), 8.07-8.15 (1H),8.47 (1H).

Example 82-{[1-(4-bromo-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 51.8 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 1a and 44.7 mg of4-bromo-2-fluorobenzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.04-1.27 (2H), 1.32-1.43 (1H),1.49-1.61 (1H), 2.20-2.33 (1H), 2.48 (3H), 2.67-2.80 (1H), 2.91-3.05(1H), 3.24 (3H), 3.33-3.46 (5H), 4.24-4.36 (2H), 4.38-4.49 (1H), 7.15(1H), 7.27-7.34 (1H), 7.35-7.41 (1H), 7.44-7.50 (1H), 7.60-7.66 (1H),8.07-8.15 (1H), 8.47 (1H).

Example 92-{[1-(2-fluoro-4-methylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 38.3 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 1a and 31.5 mg of2-fluoro-4-methylbenzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.04-1.26 (2H), 1.31-1.43 (1H),1.48-1.60 (1H), 2.18-2.35 (4H), 2.48 (3H), 2.64-2.79 (1H), 2.89-3.04(1H), 3.24 (3H), 3.33-3.39 (3H), 3.39-3.45 (2H), 4.23-4.36 (2H),4.39-4.49 (1H), 7.01-7.10 (2H), 7.13 (1H), 7.16-7.24 (1H), 7.38 (1H),8.07-8.14 (1H), 8.47 (1H).

Example 102-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 57.8 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 1a and 42.5 mg of2-fluoro-4-(trifluoromethyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.07-1.29 (2H), 1.32-1.44 (1H),1.52-1.62 (1H), 2.20-2.36 (1H), 2.49 (3H), 2.67-2.84 (1H), 2.93-3.07(1H), 3.24 (3H), 3.32-3.39 (3H), 3.39-3.46 (2H), 4.24-4.39 (2H),4.40-4.51 (1H), 7.14 (1H), 7.38 (1H), 7.56-7.68 (2H), 7.76 (1H),8.07-8.14 (1H), 8.47 (1H).

Example 11N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pentafluoro-AP-sulphanyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 135.1 mg of the title compound was obtainedfrom 150 mg of the amine prepared in Example 1a and 101.5 mg of4-(pentafluoro-λ⁶-sulphanyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.10-1.30 (2H), 1.31-1.42 (1H),1.50-1.62 (1H), 2.20-2.33 (1H), 2.49 (3H), 2.67-2.83 (1H), 2.91-3.06(1H), 3.24 (3H), 3.32-3.39 (2H), 3.41 (3H), 4.32 (2H), 4.37-4.48 (1H),7.14 (1H), 7.38 (1H), 7.55 (2H), 7.94 (2H), 8.12 (1H), 8.47 (1H).

The following compounds were prepared analogously:

Ex. Structure IUPAC name Analysis 12

N-(2-methoxyethyl)- 4-methyl-2-{[1-(4- methylbenzoyl)- piperidin-4-yl]-methyl}-2H- indazole-5- carboxamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =1.20 (2H), 1.42 (2H), 2.29 (4H), 2.49 (3H), 2.73 (1H), 2.93 (1H), 3.25(3H), 3.37 (2H), 3.43 (2H), 3.57 (1H), 4.31 (2H), 4.40 (1H), 7.14 (1H),7.21 (4H), 7.38 (1H), 8.09 (1H), 8.46 (1H). 13

N-(2-methoxyethyl)- 4-methyl-2-({1-[(3- phenylisoxazol-5-yl)carbonyl]piperidin- 4-yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR(300 MHz, DMSO-d₆): δ [ppm] = 1.25 (2H), 1.55 (2H), 2.34 (1H), 2.49(3H), 2.83 (1H), 3.15 (1H), 3.24 (3H), 3.40 (4H), 3.87 (1H), 4.35 (3H),7.15 (1H), 7.40 (1H), 7.46 (1H), 7.50 (3H), 7.90 (2H), 8.13 (1H), 8.49(1H). 14

2-({1-[4-(4-chloro- phenoxy)benzoyl]- piperidin-4-yl}- methyl)-N-(2-methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm] = 1.21 (2H), 1.45 (2H), 2.26 (1H), 2.49 (3H), 2.76(1H), 2.94 (1H), 3.24 (3H), 3.40 (4H), 3.62 (1H), 4.33 (3H), 7.04 (4H),7.15 (1H), 7.40 (5H), 8.12 (1H), 8.47 (1H). 15

N-(2-methoxyethyl)- 4-methyl-2-({1-[4-(4- methylphenoxy)-benzoyl]piperidin-4- yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR (300MHz, DMSO-d₆): δ [ppm], 1.20 (2H), 1.43 (2H), 2.26 (4H), 2.48 (3H), 2.76(1H), 2.90 (1H), 3.24 (3H), 3.38 (4H), 3.62 (1H), 4.32 (3H), 6.92 (4H),7.71 (3H), 7.34 (3H), 8.12 (1H), 8.47 (1H). 16

2-({1-[4-(4-tert- butylphenoxy)- benzoyl]piperidin-4- yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm], 1.21 (2H), 1.25 (9H), 1.44 (2H), 2.26 (1H), 2.48(3H), 2.77 (1H), 2.291 (1H), 3.24 (3H), 3.39 (4H), 3.64 (1H), 4.32 (3H),6.95 (4H), 7.14 (1H), 7.36 (5H), 8.12 (1H), 8.47 (1H). 17

N-(2-methoxyethyl)- 4-methyl-2-[(1-{4-[4- (trifluoromethyl)-phenoxy]benzoyl}- piperidin-4-yl)- methyl]-2H-indazole- 5-carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.22 (2H), 1.45 (2H), 2.27 (1H),2.49 (3H), 2.77 (1H) 2.97 (1H), 3.24 (3H), 3.39 (4H), 3.61 (1H), 4.33(3H), 7.15 (5H), 7.39 (3H), 7.73 (2H), 8.12 (1H), 8.48 (1H). 18

N-(2-methoxyethyl)- 2-({1-[4-(4-methoxy- phenoxy)benzoyl]-piperidin-4-yl}- methyl)-4-methyl- 2H-indazole-5- carboxamide ¹H-NMR(300 MHz, DMSO-d₆): δ [ppm] = 1.19 (2H), 1.44 (2H), 2.25 (1H), 2.48(3H), 2.86 (2H), 3.24 (3H), 3.40 (4H), 3.64 (1H), 3.72 (3H), 4.32 (3H),6.88 (2H), 6.95 (2H), 7.02 (2H), 7.14 (1H), 7.31 (2H), 7.38 (1H), 8.12(1H), 8.47 (1H). 19

N-(2-methoxyethyl)- 4-methyl-2-{[1-(4- phenoxybenzoyl)- piperidin-4-yl]-methyl}-2H- indazole-5- carboxamide ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] =1.21 (2H), 1.44 (2H), 2.26 (1H), 2.49 (3H), 2.77 (1H), 2.92 (1H), 3.24(3H), 3.38 (4H), 3.64 (1H), 4.32 (3H), 6.97 (2H), 7.04 (2H), 7.16 (2H),7.26 (5H), 8.12 (1H), 8.47 (1H). 20

2-{[1-(4-cyclopropyl- benzoyl)piperidin-4- yl]methyl}-N-(2-methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide 1H-NMR (300 MHz,DMSO-d₆): δ [ppm] = 0.65 (2H), 0.93 (2H), 1.19 (2H), 1.43 (2H), 1.90(1H), 2.25 (1H), 2.48 (3H), 2.73 (1H), 2.92 (1H), 3.24 (3H), 3.39 (4H),3.59 (1H), 4.32 (3H), 7.14 (5H), 7.38 (1H), 8.12 (1H), 8.47 (1H). 21

2-{[1-(4-methoxy- benzoyl)piperidin-4- yl]methyl}-N-(2- methoxyethyl)-4-methyl-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =1.19 (2H), 1.44 (2H), 2.26 (1H), 2.49 (3H), 2.82 (2H), 3.24 (3H), 3.36(2H), 3.42 (2H), 3.50 (1H), 3.74 (3H), 4.31 (3H), 6.93 (2H), 7.14 (1H),7.29 (2H), 7.38 (1H), 8.12 (1H), 8.47 (1H). 22

2-{[1-(4-fluoro- benzoyl)piperidin-4- yl]methyl}-N-(2- methoxyethyl)-4-methyl-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =1.20 (2H), 1.37 (1H), 1.51 (1H), 2.27 (1H), 2.49 (3H), 2.72 (1H), 2.97(1H), 3.24 (3H), 3.36 (2H), 3.42 (2H), 3.52 (1H), 4.31 (2H), 4.40 (1H),7.14 (1H), 7.23 (2H), 7.39 (3H), 8.12 (1H), 8.47 (1H). 23

N-(2-methoxyethyl)- 4-methyl-2-({1-[4- (trifluoromethyl)-benzoyl]piperidin-4- yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 1.22 (2H), 1.34 (1H), 1.56 (1H), 2.28 (1H),2.49 (3H), 2.75 (1H), 2.99 (1H), 3.24 (3H), 3.35 (2H), 3.42 (3H), 4.32(2H), 4.44 (1H), 7.14 (1H), 7.38 (1H), 7.55 (2H), 7.77 (2H), 8.12 (1H),8.47 (1H). 24

2-{[1-(2-methoxy- benzoyl)piperidin-4- yl]methyl}-N-(2- methoxyethyl)-4-methyl-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =1.11 (2H), 1.35 (1H), 1.52 (1H), 2.23 (1H), 2.49 (3H), 2.66 (1H), 2.87(1H), 3.22 (1H), 3.24 (3H), 3.35 (2H), 3.42 (2H), 3.71 (3H), 4.29 (1H),4.33 (1H), 4.45 (1H), 6.94 (1H), 7.07 (3H), 7.33 (1H), 7.39 (1H), 8.12(1H), 8.48 (1H). 25

N-(2-methoxyethyl)- 4-methyl-2-[(1-{4- [(trifluoromethyl)-sulphonyl]benzoyl}- piperidin-4-yl)- methyl]-2H-indazole- 5-carboxamide¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.23 (2H), 1.36 (1H), 1.57 (1H),2.29 (1H), 2.49 (3H), 2.77 (1H), 3.01 (1H), 3.24 (3H), 3.35 (3H), 3.42(2H), 4.32 (2H), 4.44 (1H), 7.14 (1H), 7.38 (1H), 7.77 (2H), 8.15 (3H),8.47 (1H). 26

N-(2-methoxyethyl)- 4-methyl-2-({1-[3- (trifluoromethyl)-benzoyl]piperidin-4- yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 1.24 (2H), 1.37 (1H), 1.55 (1H), 2.28 (1H),2.49 (3H), 2.75 (1H), 3.01 (1H), 3.24 (3H), 3.36 (2H), 3.42 (3H), 4.32(2H), 4.43 (1H), 7.14 (1H), 7.38 (1H), 7.65 (3H), 7.78 (1H), 8.12 (1H),8.47 (1H). 27

N-(2-methoxyethyl)- 4-methyl-2-{[1-(3- methylbenzoyl)- piperidin-4-yl]-methyl}-2H- indazole-5- carboxamide 1H-NMR (400 MHz, DMSO-d₆): δ [ppm] =1.20 (2H), 1.36 (1H), 1.52 (1H), 2.29 (4H), 2.49 (3H), 2.69 (1H), 2.95(1H), 3.24 (3H), 3.36 (2H), 3.42 (2H), 3.53 (1H), 4.31 (2H), 4.41 (1H),7.12 (3H), 7.21 (1H), 7.27 (1H), 7.38 (1H), 8.12 (1H), 8.47 (1H). 28

2-{[1-(3-chloro- benzoyl)piperidin-4- yl]methyl}-N-(2- methoxyethyl)-4-methyl-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =1.21 (2H), 1.36 (1H), 1.53 (1H), 2.27 (1H), 2.49 (3H), 2.72 (1H), 2.98(1H), 3.24 (3H), 3.35 (2H), 3.42 (3H), 4.31 (2H), 4.40 (1H), 7.14 (1H),7.28 (1H), 7.43 (4H), 8.12 (1H), 8.47 (1H). 29

N-(2-methoxyethyl)- 4-methyl-2-({1-[(1- methyl-1H-indol-2- yl)carbonyl]-piperidin-4- yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 1.25 (2H), 1.50 (2H), 2.31 (1H), 2.49 (3H), 2.82(1H), 3.05 (1H), 3.24 (3H), 3.36 (2H), 3.42 (2H), 3.69 (3H), 3.98 (1H),4.34 (2H), 4.44 (1H), 6.57 (1H), 7.05 (1H), 7.15 (1H), 7.20 (1H), 7.39(1H), 7.46 (1H), 7.56 (1H), 8.12 (1H), 8.49 (1H). 30

2-({1-[4-(4- carbamoylphenoxy)- benzoyl]piperidin-4- yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 1.22 (2H), 1.49 (2H), 2.31 (1H), 2.52 (3H), 2.82(1H), 2.98 (1H), 3.27 (3H), 3.39 (2H), 3.45 (2H), 3.65 (1H), 4.35 (2H),4.43 (1H), 7.08 (4H), 7.17 (1H), 7.29 (1H), 7.41 (3H), 7.91 (3H), 8.12(1H), 8.50 (1H). 31

2-({1-[4-(cyclo- pentyloxy)benzoyl]- piperidin-4-yl}- methyl)-N-(2-methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 1.23 (2H), 1.47 (2H), 1.57 (2H), 1.68 (4H), 1.90(2H), 2.28 (1H), 2.52 (3H), 2.86 (2H), 3.27 (3H), 3.39 (2H), 3.45 (2H),3.85 (2H), 4.34 (2H), 4.83 (1H), 6.91 (2H), 7.17 (1H), 7.28 (2H), 7.41(1H), 8.12 (1H), 8.49 (1H). 32

2-({1-[4-(difluoro- methyl)benzoyl]- piperidin-4-yl}- methyl)-N-(2-methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 1.24 (2H), 1.39 (1H), 1.57 (1H), 2.30 (1H), 2.52(3H), 2.76 (1H), 3.01 (1H), 3.27 (3H), 3.39 (2H), 3.45 (3H), 4.35 (2H),4.45 (1H), 7.18 (2H), 7.41 (1H), 7.49 (2H), 7.62 (2H), 8.12 (1H), 8.49(1H). 33

2-{[1-(4-cyano- benzoyl)piperidin-4- yl]methyl}-N-(2- methoxyethyl)-4-methyl-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =1.24 (2H), 1.39 (1H), 1.58 (1H), 2.30 (1H), 2.52 (3H), 2.77 (1H), 3.01(1H), 3.27 (3H), 3.39 (3H), 3.45 (2H), 4.34 (2H), 4.44 (1H), 7.17 (1H),7.41 (1H), 7.54 (2H), 7.90 (2H), 8.12 (1H), 8.49 (1H). 34

2-({1-[4-(1H- imidazol-1-yl)- benzoyl]piperidin-4- yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm] = 1.24 (2H), 1.39 (1H), 156 (1H), 2.29 (1H), 2.49(3H), 2.76 (1H), 3.04 (1H), 3.24 (3H), 3.37 (3H), 3.42 (3H), 4.33 (2H),4.44 (1H), 7.15 (1H), 7.39 (1H), 7.61 (2H), 7.84 (3H), 8.11 (1H), 8.26(1H), 8.48 (1H). 35

N-(2-methoxyethyl)- 4-methyl-2-({1-[4- (oxazol-2-yl)-benzoyl]piperidin-4- yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR (300MHz, DMSO-d₆): δ [ppm] = 1.24 (2H), 1.37 (1H), 1.54 (1H), 2.27 (1H),2.49 (3H), 2.75 (1H), 3.00 (1H), 3.24 (3H), 3.36 (2H), 3.42 (2H), 3.53(1H), 4.32 (2H), 4.43 (1H), 7.14 (1H), 7.38 (2H), 7.48 (2H), 8.00 (2H),8.12 (1H), 8.23 (1H), 8.48 (1H). 36

N-(2-methoxyethyl)- 4-methyl-2-({1-[4- (oxazol-5-yl)-benzoyl]piperidin-4- yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR (300MHz, DMSO-d₆): δ [ppm] = 1.22 (2H), 1.38 (1H), 1.53 (1H), 2.28 (1H),2.49 (3H), 2.74 (1H), 2.98 (1H), 3.24 (3H), 3.36 (2H), 3.41 (2H), 3.55(1H), 4.32 (2H), 4.41 (1H), 7.15 (1H), 7.42 (3H), 7.74 (3H), 8.12 (1H),8.47 (2H). 37

N-(2-methoxyethyl)- 4-methyl-2-({1-[4- (isoxazol-5-yl)-benzoyl]piperidin-4- yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR (300MHz, DMSO-d₆): δ [ppm] = 1.22 (2H), 1.36 (1H), 1.55 (1H), 2.28 (1H),2.49 (3H), 2.74 (1H), 2.99 (1H), 3.24 (3H), 3.39 (5H), 4.31 (2H), 4.43(1H), 4.74 (2H), 7.14 (1H), 7.38 (1H), 7.50 (2H), 7.95 (2H), 8.12 (1H),8.47 (1H). 38

N-(2-methoxyethyl)- 4-methyl-2-({1-[4- (1H-pyrazol-1-yl)-benzoyl]piperidin-4- yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR (300MHz, DMSO-d₆): δ [ppm] = 1.22 (2H), 1.46 (2H), 2.28 (1H), 2.49 (3H),2.76 (1H), 2.99 (1H), 3.24 (3H), 3.39 (4H), 3.61 (1H), 4.32 (2H), 4.41(1H), 6.54 (1H), 7.15 (1H), 7.39 (1H), 7.46 (2H), 7.74 (1H), 7.87 (2H),8.12 (1H), 8.50 (2H). 39

N-(2-methoxyethyl)- 4-methyl-2-({1-[4- (1H-1,2,4-triazol-1-yl)benzoyl]piperidin- 4-yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR(300 MHz, DMSO-d₆): δ [ppm] = 1.22 (2H), 1.39 (1H), 1.53 (1H), 2.27(1H), 2.49 (3H), 2.76 (1H), 3.00 (1H), 3.24 (3H), 3.39 (4H), 3.54 (1H),4.32 (2H), 4.43 (1H), 7.15 (1H), 7.39 (1H), 7.53 (2H), 7.90 (2H), 8.12(1H), 8.24 (1H), 8.48 (1H), 9.32 (1H). 40

2-({1-[4-(difluoro- methoxy)-2-fluoro- benzoyl]piperidin-4-yl}methyl)-N-(2- methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.16 (2H), 1.38 (1H), 1.55 (1H),2.26 (1H), 2.48 (3H), 2.73 (1H), 2.98 (1H), 3.24 (3H), 3.38 (5H), 4.31(2H), 4.44 (1H), 7.12 (3H), 7.31 (1H), 7.40 (2H), 8.12 (1H), 8.47 (1H).41

2-({1-[2-fluoro-4- (pyrrolidin-1-yl)- benzoyl]piperidin-4-yl}methyl)-N-(2- methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.14 (2H), 1.43 (2H), 1.90 (4H),2.23 (1H), 2.48 (3H), 2.68 (1H), 2.94 (1H), 3.19 (4H), 3.24 (3H), 3.36(2H), 3.42 (3H), 4.31 (2H), 4.39 (1H), 6.29 (2H), 7.10 (2H), 7.38 (1H),8.12 (1H), 8.47 (1H). 42

2-({1-[(3,4′-difluoro- biphenyl-4-yl)- carbonyl]piperidin-4-yl}methyl)-N-(2- methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.19 (2H), 1.39 (1H), 1.57 (1H),2.28 (1H), 2.49 (3H), 2.76 (1H), 3.01 (1H), 3.24 (3H), 3.38 (5H), 4.32(2H), 4.47 (1H), 7.15 (1H), 7.28 (2H), 7.40 (2H), 7.56 (2H), 7.76 (2H),8.12 (1H), 8.48 (1H). 43

2-({1-[(3-fluoro-4′- methoxybiphenyl-4- yl)carbonyl]piperidin-4-yl}methyl)-N-(2- methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.19 (2H), 1.39 (1H), 1.57 (1H),2.28 (1H), 2.49 (3H), 2.76 (1H), 3.01 (1H), 3.24 (3H), 3.38 (5H), 4.32(2H), 4.47 (1H), 7.15 (1H), 7.28 (2H), 7.40 (2H), 7.56 (2H), 7.76 (2H),8.12 (1H), 8.48 (1H). 44

2-({1-[(3-fluoro-4′- methylbiphenyl-4- yl)carbonyl]piperidin-4-yl}methyl)-N-(2- methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.19 (2H), 1.39 (1H), 1.57 (1H),2.31 (4H), 2.49 (3H), 2.75 (1H), 3.01 (1H), 3.24 (3H), 3.36 (2H), 3.42(3H), 4.32 (2H), 4.48 (1H), 7.14 (1H), 7.26 (2H), 7.39 (2H), 7.56 (4H),8.12 (1H), 8.48 (1H). 45

2-[(1-{[3-fluoro-3′- (trifluoromethyl)- biphenyl-4-yl]-carbonyl}-piperidin- 4-yl)-methyl]-N-(2- methoxyethyl)-4-methyl-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =1.20 (2H), 1.40 (1H), 1.57 (1H), 2.29 (1H), 2.49 (3H), 2.76 (1H), 3.03(1H), 3.24 (3H), 3.36 (2H), 3.41 (3H), 4.33 (2H), 4.48 (1H), 7.15 (1H),7.39 (1H), 7.45 (1H), 7.69 (4H), 8.03 (2H), 8.12 (1H), 8.49 (1H). 46

2-[(1-{[3-fluoro-2′- (trifluoromethoxy)- biphenyl-4-yl]-carbonyl}piperidin-4- yl)methyl]-N-(2- methoxyethyl)-4-methyl-2H-indazole- 5-carboxamide ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] =1.20 (2H), 1.42 (1H), 1.57 (1H), 2.29 (1H), 2.49 (3H), 2.76 (1H), 3.04(1H), 3.24 (3H), 3.36 (5H), 4.32 (2H), 4.48 (1H), 7.15 (1H), 7.44 (8H),8.12 (1H), 8.49 (1H). 47

2-({1-[(2′-fluoro- biphenyl-4-yl)- carbonyl]piperidin-4-yl}methyl)-N-(2- methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.23 (2H), 1.41 (1H), 1.53 (1H),2.29 (1H), 2.49 (3H), 2.74 (1H), 3.01 (1H), 3.24 (3H), 3.36 (4H), 3.60(1H), 4.33 (2H), 4.44 (1H), 7.15 (1H), 7.29 (2H), 7.40 (4H), 7.55 (3H),8.12 (1H), 8.48 (1H). 48

2-({1-[(2′,4′-difluoro- biphenyl-4-yl)- carbonyl]piperidin-4-yl}methyl)-N-(2- methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.23 (2H), 1.39 (1H), 1.53 (1H),2.28 (1H), 2.49 (3H), 2.75 (1H), 3.01 (1H), 3.24 (3H), 3.39 (4H), 3.60(1H), 4.33 (2H), 4.43 (1H), 7.16 (2H), 7.40 (4H), 7.56 (3H), 8.12 (1H),8.48 (1H). 49

2-({1-[(2-fluoro- biphenyl-4-yl)- carbonyl]piperidin-4- yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 1.24 (2H), 1.39 (1H), 1.56 (1H), 2.29 (1H), 2.49(3H), 2.74 (1H), 3.02 (1H), 3.25 (3H), 3.37 (2H), 3.42 (2H), 3.59 (1H),4.33 (2H), 4.43 (1H), 7.15 (1H), 7.28 (2H), 7.40 (2H), 7.46 (2H), 7.54(3H), 8.12 (1H), 8.48 (1H). 50

N-(2-methoxyethyl)- 4-methyl-2-({1-[(2′- methylbiphenyl-4-yl)carbonyl]piperidin- 4-yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 1.24 (2H), 1.42 (1H), 1.55 (1H), 2.20(3H), 2.29 (1H), 2.49 (3H), 2.75 (1H), 3.02 (1H), 3.25 (3H), 3.37 (2H),3.42 (2H), 3.64 (1H), 4.33 (2H), 4.42 (1H), 7.21 (5H), 7.38 (5H), 8.12(1H), 8.49 (1H). 51

N-(2-methoxyethyl)- 4-methyl-2-({1-[4- (pyridyloxy)benzoyl]-piperidin-4-yl}- methyl)-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 1.24 (2H), 1.42 (1H), 1.55 (1H), 2.29 (1H), 2.49(3H), 2.76 (1H), 3.02 (1H), 3.25 (3H), 3.37 (2H), 3.43 (2H), 3.60 (1H),4.33 (2H), 4.44 (1H), 7.15 (1H), 7.37 (3H), 7.48 (2H), 7.53 (2H), 8.12(1H), 8.48 (1H), 8.75 (2H). 52

N-(2-methoxyethyl)- 4-methyl-2-({1-[4- (4H-1,2,4-triazol-4-yl)benzoyl]piperidin- 4-yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 1.23 (2H), 1.38 (1H), 1.54 (1H), 2.28(1H), 2.49 (3H), 2.74 (1H), 3.02 (1H), 3.24 (3H), 3.36 (2H), 3.42 (2H),3.53 (1H), 4.32 (2H), 4.42 (1H), 7.14 (1H), 7.38 (1H), 7.55 (2H), 7.75(2H), 8.14 (1H), 8.48 (1H), 9.15 (2H). 53

2-({1-[2-fluoro-4- (morpholin-4- yl)benzoyl]- piperidin-4-yl}-methyl)-N-(2- methoxyethyl)-4- methyl-2H-indazole- 5-carboxamide ¹H-NMR(600 MHz, DMSO-d₆): δ [ppm] = 1.01 (1H), 1.21 (1H), 1.36 (1H), 1.48(1H), 1.57 (1H), 2.08 (1H), 2.53 (3H), 2.96 (7H), 3.29 (3H), 3.41 (2H),3.47 (2H), 3.67 (4H), 4.34 (2H), 4.50 (1H), 6.86 (2H), 7.14 (2H), 7.41(1H), 8.11 (1H), 8.47 (1H), 8.56 (1H). 54

2-{[1-(4-bromo- benzoyl)piperidin-4- yl]methyl}-N-(2- methoxyethyl)-4-methyl-2H-indazole- 5-carboxamide ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] =1.22 (2H), 1.36 (1H), 1.52 (1H), 2.26 (1H), 2.49 (3H), 2.72 (1H), 2.97(1H), 3.24 (3H), 3.36 (2H), 3.42 (2H), 3.49 (1H), 4.31 (2H), 4.40 (1H),7.14 (1H), 7.29 (2H), 7.38 (1H), 7.60 (2H), 8.12 (1H), 8.47 (1H).

Example 55N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

150 mg of the amine prepared in Example 1a were first dissolved in 1.5ml pyridine. 101 mg of 4-(trifluoromethoxy)benzoyl chloride were thenadded and the mixture stirred for 30 min at RT. The reaction mixture wasthen treated with some toluene and concentrated. The residue was takenup in ethyl acetate and washed twice with water, twice with saturatedsodium hydrogen carbonate solution (pH 9) and once with saturated sodiumchloride solution. The organic phase was dried over sodium sulphate,filtered and concentrated. The residue was purified chromatographicallyon the Biotage SP4. Gradient: ethyl acetate/methanol 0-10%. Yield: 118.2mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): □ [ppm], 1.17-1.30 (2H), 1.30-1.45 (1H),1.45-1.62 (1H), 2.19-2.35 (1H), 2.49 (3H), 2.64-2.86 (1H), 2.86-3.07(1H), 3.24 (3H), 3.31-3.56 (5H), 4.31 (2H), 4.36-4.49 (1H), 7.14 (1H),7.35-7.42 (3H), 7.43-7.50 (2H), 8.11 (1H), 8.47 (1H).

Example 562-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 183 mg of the title compound was obtainedfrom 300 mg of the amine prepared in Example 1a and 157.4 mg of4-chlorobenzoyl chloride.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.10-1.29 (2H), 1.29-1.43 (1H),1.44-1.61 (1H), 2.20-2.34 (1H), 2.49 (3H), 2.66-2.83 (1H), 2.84-3.06(1H), 3.25 (3H), 3.32-3.39 (2H), 3.40-3.45 (2H), 3.45-3.55 (1H),4.26-4.35 (2H), 4.35-4.46 (1H), 7.14 (1H), 7.32-7.41 (3H), 7.47 (2H),8.09-8.15 (1H), 8.47 (1H).

Example 57N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

60 mg of the amine prepared in Example 1a were first dissolved in 2 mlDCM at 0° C. 0.034 ml of triethylamine and 43.2 mg of4-[(trifluoromethyl)sulphanyl]benzoyl chloride were then added and themixture stirred for 2 hrs at 0° C. The reaction mixture was then dilutedwith DCM and washed with 1-molar hydrochloric acid, saturated sodiumhydrogen carbonate solution (pH 9) and saturated sodium chloridesolution. The organic phase was dried over sodium sulphate, filtered andconcentrated. The residue was purified chromatographically on theBiotage SP4. Gradient: DCM/Methanol 0-10%. The product fraction wastaken up in ethyl acetate and extracted twice with saturated sodiumhydrogen carbonate solution. The organic phase was concentrated and theresidue again purified by HPLC. Yield: 26.5 mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.14-1.30 (2H), 1.31-1.42 (1H),1.49-1.61 (1H), 2.21-2.32 (1H), 2.49 (3H), 2.67-2.80 (1H), 2.93-3.05(1H), 3.25 (3H), 3.36 (2H), 3.42 (3H), 4.27-4.36 (2H), 4.38-4.48 (1H),7.14 (1H), 7.38 (1H), 7.48 (2H), 7.75 (2H), 8.09-8.14 (1H), 8.47 (1H).

Example 582-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2-morpholinoethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 34.6 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 58a and 37.0 mg of2-fluoro-4-(trifluoromethyl)benzoic acid.

¹H-NMR (400 MHz, methanol-d₄): δ [ppm], 1.24-1.43 (2H), 1.50-1.59 (1H),1.65-1.73 (1H), 2.33-2.45 (1H), 2.65 (3H), 2.80-2.91 (1H), 3.05-3.18(1H), 3.19-3.26 (2H), 3.39-3.44 (2H), 3.45-3.52 (1H), 3.63-3.70 (2H),3.71-3.82 (4H), 4.06-4.14 (2H), 4.39 (2H), 4.62-4.70 (1H), 7.39 (1H),7.47 (1H), 7.54-7.62 (3H), 8.45 (1H).

The starting material was prepared as follows:

Example 58a4-methyl-N-(2-morpholinoethyl)-2-(4-piperidylmethyl)-2H-indazol-5-carboxamidehydrochloride

To 624.4 mg of 58b were added 2.9 ml of 4M hydrochloric acid in dioxanand 0.5 ml dioxan. An oily mass was formed, which dissolved on vigorousstirring and gentle warming. The mixture was stirred for 1 hr at ca. 30°C. The reaction mixture was concentrated. Yield: 980 mg of the titlecompound, which was further reacted without further purification.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.33-1.51 (2H), 1.58-1.64 (1H),2.17-2.31 (1H), 2.55 (3H), 2.70-2.86 (2H), 3.02-3.31 (7H), 3.43-3.51(2H), 3.61-3.71 (2H), 3.72-3.88 (3H), 3.89-3.99 (2H), 4.30-4.36 (2H),7.29 (1H), 7.40 (1H), 8.46-8.52 (1H), 8.54-8.58 (1H), 8.69-8.85 (1H),8.96-9.10 (1H).

Example 58b Tert-butyl4-({4-methyl-5-[N-(2-morpholinoethyl)carbamoyl]-1H-indazol-2-yl}-methyl)piperidin-1-carboxylate

896 mg of 1c, 857 mg of 2-morpholinoethylamine, 579.3 mg of molybdenumhexacarbonyl, 63.6 mg of tri-tert-butylphosphine tetrafluoroborate and205.8 mg oftrans-bis(acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)were placed in a microwave tube and suspended in 18 ml THF. 1.0 ml ofDBU was then added and the mixture was stirred for 20 mins at 125° C.and 200 watts in the microwave. The reaction mixture was diluted withsome ethyl acetate and firstly filtered through Celite. The filtrate wasdiluted with ethyl acetate and the organic phase washed twice with waterand once with saturated sodium chloride solution. It was then dried oversodium sulphate, filtered and concentrated. The residue waschromatographed on the Biotage SP4. Gradient: ethyl acetate/methanol0-10%. Yield: 624.4 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.98-1.13 (2H), 1.34 (11H),2.05-2.27 (2H), 2.33-2.41 (5H), 2.51 (3H), 2.56-2.73 (2H), 3.25-3.37(2H), 3.51-3.57 (4H), 3.81-3.93 (2H), 4.28 (2H), 7.14 (1H), 7.36-7.41(1H), 7.95-8.02 (1H), 8.46 (1H).

Example 594-methyl-N-(2-morpholinoethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 10.1 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 58a and 43.9 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (400 MHz, methanol-d₄): δ [ppm], 1.24-1.44 (2H), 1.44-1.58 (1H),1.59-1.74 (1H), 2.32-2.44 (1H), 2.51-2.58 (4H), 2.59-2.65 (5H),2.77-2.90 (1H), 3.02-3.17 (1H), 3.53 (2H), 3.62-3.72 (5H), 4.35-4.41(2H), 4.55-4.67 (1H), 7.29 (1H), 7.34 (2H), 7.43 (1H), 7.49 (2H), 8.39(1H).

Example 604-methyl-N-(2-morpholinoethyl)-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 14.0 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 58a and 44.1 mg of4-(pentafluoro-λ⁶-sulphanyl)benzoic acid.

¹H-NMR (400 MHz, chloroform-d): δ [ppm], 1.16-1.32 (1H), 1.33-1.48 (1H),1.50-1.63 (1H), 1.71-1.83 (1H), 1.84-2.08 (2H), 2.44 (1H), 2.55 (4H),2.60-2.71 (5H), 2.72-2.85 (1H), 2.96-3.10 (1H), 3.60 (2H), 3.67-3.78(4H), 4.33 (2H), 4.71-4.81 (1H), 6.45 (1H), 7.34 (1H), 7.47 (2H), 7.54(1H), 7.79 (2H), 7.96 (1H).

Example 614-methyl-N-(2-morpholinoethyl)-2-({1-[3-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 18.1 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 58a and 43.9 mg of3-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (400 MHz, chloroform-d): δ [ppm], 1.18-1.46 (2H), 1.49-1.63 (1H),1.66-1.82 (1H), 2.37-2.49 (1H), 2.62 (3H), 2.67 (3H), 2.70-2.78 (4H),2.79-2.86 (2H), 2.93-3.09 (1H), 3.66-3.74 (2H), 3.83 (4H), 4.32 (2H),4.66-4.82 (1H), 6.83-6.96 (1H), 7.23-7.29 (2H), 7.29-7.34 (1H), 7.39(1H), 7.43 (1H), 7.54 (1H), 7.96 (1H).

Example 622-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(2-morpholinoethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 14.9 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 58a and 34.2 mg of4-chlorobenzoyl chloride.

¹H-NMR (400 MHz, methanol-d₄): δ [ppm], 1.24-1.42 (2H), 1.46-1.58 (1H),1.58-1.71 (1H), 2.31-2.43 (1H), 2.63 (5H), 2.65 (3H), 2.73-2.91 (1H),3.00-3.15 (1H), 3.25-3.33 (2H), 3.63-3.77 (3H), 3.79-4.03 (3H), 4.38(2H), 4.54-4.67 (1H), 7.38 (3H), 7.42-7.49 (3H), 8.44 (1H).

Example 634-methyl-N-(2-morpholinoethyl)-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 31.7 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 58a and 33.8 mg of4-(trifluoromethyl)benzoic acid.

¹H-NMR (400 MHz, methanol-d4): δ [ppm], 1.24-1.43 (2H), 1.45-1.57 (1H),1.63-1.73 (1H), 2.33-2.45 (1H), 2.66 (3H), 2.79-2.90 (1H), 3.04-3.17(1H), 3.18-3.27 (2H), 3.39-3.45 (2H), 3.56-3.70 (3H), 3.76 (4H),4.06-4.14 (2H), 4.36-4.42 (2H), 4.59-4.68 (1H), 7.39 (1H), 7.47 (1H),7.57 (2H), 7.73 (2H), 8.45 (1H).

Example 644-methyl-N-(2-morpholinoethyl)-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 24.7 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 58a and 44.1 mg of3-(pentafluoro-λ⁶-sulphanyl)benzoic acid.

¹H-NMR (400 MHz, methanol-d₄): δ [ppm], 1.27-1.47 (2H), 1.48-1.60 (1H),1.60-1.74 (1H), 2.31-2.46 (1H), 2.66 (3H), 2.78-2.93 (1H), 3.04-3.18(1H), 3.18-3.26 (2H), 3.39-3.43 (2H), 3.57-3.70 (3H), 3.72-3.82 (4H),4.06-4.14 (2H), 4.39 (2H), 4.55-4.67 (1H), 7.38 (1H), 7.47 (1H),7.60-7.67 (2H), 7.82-7.86 (1H), 7.89-7.94 (1H), 8.45 (1H).

Example 654-methyl-N-(2-morpholinoethyl)-2-({1-[3-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 14.0 mg of the title compound was obtainedfrom 75 mg of the amine prepared in Example 58a and 33.8 mg of3-(trifluoromethyl)benzoic acid.

¹H-NMR (400 MHz, methanol-d₄): δ [ppm], 1.28-1.45 (2H), 1.47-1.59 (1H),1.59-1.73 (1H), 2.32-2.45 (1H), 2.66 (3H), 2.79-2.93 (1H), 3.05-3.18(1H), 3.19-3.27 (2H), 3.39-3.45 (2H), 3.58-3.70 (3H), 3.72-3.82 (4H),4.06-4.14 (2H), 4.39 (2H), 4.57-4.68 (1H), 7.39 (1H), 7.47 (1H), 7.64(2H), 7.67-7.70 (1H), 7.73-7.78 (1H), 8.45 (1H).

The following compounds were prepared analogously:

Ex. Structure IUPAC name Analysis 66

2-({1-[(4′-fluoro- biphenyl-4-yl)- carbonyl]piperidin-4-yl}methyl)-4-methyl- N-(2-morpholino- ethyl)-2H-indazole-5- carboxamide1H-NMR (400 MHz, methanol- d₄): δ [ppm] = 1.35 (2H), 1.53 (1H), 1.66(1H), 2.40 (1H), 2.66 (3H), 2.85 (1H), 3.11 (1H), 3.24 (2H), 3.42 (2H),3.65 (2H), 3.76 (5H), 4.08 (2H), 4.40 (2H), 4.63 (1H), 7.17 (2H), 7.38(1H), 7.47 (3H), 7.65 (4H), 8.45 (1H). 67

2-({1-[4-(4-fluoro- phenoxy)benzoyl]- piperidinyl-4-yl}-methyl)-4-methyl-N- (2-morpholinoethyl)- 2H-indazole-5- carboxamide1H-NMR (400 MHz, methanol- d₄): δ [ppm] = 1.33 (2H), 1.68 (2H), 2.38(1H), 2.66 (3H), 2.84 (1H), 3.11 (1H), 3.25 (2H), 3.42 (2H), 3.65 (2H),3.76 (5H), 4.11 (2H), 4.38 (2H), 4.59 (1H), 6.98 (2H), 7.04 (2H), 7.11(2H), 7.38 (3H), 7.47 (1H), 8.44 (1H).

Example 68N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 57, 61.7 mg of the title compound was obtainedfrom 266.5 mg of the amine prepared in Example 68a and 150.3 mg of4-(pentafluoro-λ⁶-sulphanyl)benzoyl chloride.

¹H-NMR (300 MHz, chloroform-d): δ [ppm], 1.13-1.46 (2H), 1.48-1.65 (1H),1.66-1.87 (1H), 2.26-2.50 (3H), 2.66 (3H), 2.71-3.23 (8H), 3.57-3.72(3H), 4.25-4.42 (2H), 4.67-4.84 (1H), 6.40-6.61 (1H), 7.38 (1H), 7.47(2H), 7.53 (1H), 7.79 (2H), 7.96 (1H).

The starting material was prepared as follows:

Example 68aN-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamidehydrochloride

To 416.6 mg of 68b were added 1.85 ml of 4M hydrochloric acid in dioxanand 0.5 ml dioxan. An oily mass was formed, which dissolved on vigorousstirring and gentle warming. The mixture was stirred for 1 hr at ca. 30°C. The reaction mixture was concentrated. Yield: 439.2 mg of the titlecompound, which was further reacted without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.36-1.48 (2H), 1.54-1.63 (2H),2.18-2.28 (1H), 2.40-2.45 (2H), 2.55 (3H), 2.72-2.83 (2H), 3.14-3.22(2H), 3.38-3.44 (2H), 3.56-3.63 (2H), 3.65-3.95 (2H), 4.11-4.21 (2H),7.32 (1H), 7.40 (1H), 8.43-8.48 (1H), 8.57 (1H), 8.68-8.82 (1H),8.96-9.07 (1H).

Example 68b Tert-butyl4-[(5-{N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]carbamoyl}-4-methyl-2H-indazol-2-yl)methyl]-piperidin-1-carboxylate

220 mg of 1c, 242.7 mg of 2-(3,3-difluoro-pyrrolidin-1-yl)ethylamine,142.2 mg of molybdenum hexacarbonyl, 15.6 mg of tri-tert-butylphosphinetetrafluoroborate and 50.5 mg oftrans-bis(acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)were placed in a microwave tube and suspended in 4.4 ml THF. 0.24 ml ofDBU were then added and the mixture stirred for 20 mins at 125° C. and200 watts in the microwave. The reaction mixture was diluted with someethyl acetate and firstly filtered through Celite. The filtrate wasdiluted with ethyl acetate and the organic phase washed twice with waterand once with saturated sodium chloride solution. It was dried oversodium sulphate, filtered and concentrated. The residue (209.3 mg) waschromatographed on the Biotage SP4. Gradient: DCM/methanol 0-10%. Yield:53.4 mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.00-1.12 (2H), 1.32-1.42 (2H), 1.34(9H), 2.07-2.25 (3H), 2.50 (3H), 2.57 (2H), 2.60-2.68 (2H), 2.72 (2H),2.91 (2H), 3.30-3.35 (2H), 3.83-3.92 (2H), 4.28 (2H), 7.15 (1H), 7.39(1H), 8.04-8.09 (1H), 8.47 (1H).

Example 692-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 57, 79.9 mg of the title compound was obtainedfrom 125.0 mg of the amine prepared in Example 68a and 54.5 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, chloroform-d): δ [ppm], 1.13-1.35 (2H), 1.46-1.84 (2H),2.27-2.50 (3H), 2.66 (3H), 2.80-3.26 (8H), 3.59-3.83 (3H), 4.25-4.39(2H), 4.62-4.85 (1H), 6.41-6.69 (1H), 7.30-7.40 (6H), 7.55 (1H), 7.96(1H).

Example 70N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 15.2 mg of the title compound was obtainedfrom 23.4 mg of the amine prepared in Example 68a and 14.0 mg of4-[(trifluoromethyl)sulphanyl]benzoyl chloride.

¹H-NMR (400 MHz, chloroform-d): δ [ppm], 1.23-1.26 (1H), 1.33-1.46 (1H),1.48-1.61 (1H), 1.77 (1H), 2.20-2.35 (2H), 2.36-2.49 (1H), 2.64 (3H),2.73-2.85 (5H), 2.90-3.10 (3H), 3.56 (2H), 3.63-3.76 (1H), 4.26-4.39(2H), 4.70-4.82 (1H), 6.28 (1H), 7.33 (1H), 7.42 (2H), 7.53 (1H), 7.68(2H), 7.96 (1H).

Example 714-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 124.8 mg of the title compound was obtainedfrom 146.9 mg of the amine prepared in Example 71a and 93.3 mg of4-(pentafluoro-λ⁶-sulphanyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.12-1.31 (2H), 1.31-1.45 (1H),1.47-1.63 (1H), 2.20-2.36 (1H), 2.50 (3H), 2.67-2.83 (1H), 2.91-3.07(1H), 3.36-3.47 (1H), 3.96-4.10 (2H), 4.29-4.37 (2H), 4.37-4.48 (1H),7.17 (1H), 7.43 (1H), 7.56 (2H), 7.94 (2H), 8.50-8.54 (1H), 8.75-8.83(1H).

The starting material was prepared as follows:

Example 71a4-methyl-2-(4-piperidylmethyl)-N-(2,2,2-trifluoroethyl)-2H-indazol-5-carboxamidehydrochloride

To 425.2 mg of 71b were added 2.35 ml of 4M hydrochloric acid in dioxanand 0.5 ml dioxan. An oily mass was formed, which dissolved on vigorousstirring and gentle warming. The mixture was stirred for 1 hr at ca. 30°C. The reaction mixture was concentrated. Yield: 440.6 mg of the titlecompound, which was further reacted without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.35-1.49 (2H), 1.53-1.62 (2H),2.20-2.32 (1H), 2.51 (3H), 2.72-2.85 (2H), 3.14-3.23 (2H), 3.97-4.09(2H), 4.34 (2H), 7.18 (1H), 7.43 (1H), 8.58 (1H), 8.64-8.77 (1H),8.78-8.85 (1H), 8.93-9.08 (1H).

Example 71b Tert-butyl4-({4-methyl-5-[N-(2,2,2-trifluoroethyl)carbamoyl]-2H-indazol-2-yl}-methyl)piperidin-1-carboxylate

2820 mg of 1c, 2052 mg of 2,2,2-trifluoroethylamine, 1823.2 mg ofmolybdenum hexacarbonyl, 200.4 mg of tri-tert-butylphosphinetetrafluoroborate and 647.5 mg oftrans-bis(acetato)-bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II)were placed in a microwave tube and suspended in 56 ml THF. 3.1 ml ofDBU were then added and the mixture was stirred for 20 mins at 125° C.and 200 watts in the microwave. The reaction mixture was diluted withsome ethyl acetate, washed twice with water and once with saturatedsodium chloride solution. It was dried over sodium sulphate, filteredand concentrated. The residue was chromatographed on the Biotage SP4.Gradient: hexane/ethyl acetate 0-100%. Yield: 475.2 mg of the titlecompound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.99-1.17 (2H), 1.30-1.44 (11H),2.05-2.21 (1H), 2.50 (3H), 2.54-2.73 (2H), 3.81-3.94 (2H), 3.95-4.10(2H), 4.29 (2H), 7.18 (1H), 7.43 (1H), 8.51 (1H), 8.74-8.83 (1H).

Example 722-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 97.8 mg of the title compound was obtainedfrom 146.9 mg of the amine prepared in Example 71a and 58.8 mg of4-chlorobenzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.11-1.29 (2H), 1.31-1.45 (1H),1.45-1.61 (1H), 2.20-2.35 (1H), 2.50 (3H), 2.63-2.84 (1H), 2.85-3.08(1H), 3.42-3.59 (1H), 3.96-4.10 (2H), 4.29-4.47 (3H), 7.17 (1H), 7.36(2H), 7.40-7.50 (3H), 8.52 (1H), 8.75-8.82 (1H).

Example 734-methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 105.4 mg of the title compound was obtainedfrom 146.9 mg of the amine prepared in Example 71a and 77.5 mg of4-(trifluoromethoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.12-1.30 (2H), 1.31-1.46 (1H),1.47-1.64 (1H), 2.20-2.36 (1H), 2.50 (3H), 2.66-2.85 (1H), 2.86-3.09(1H), 3.40-3.55 (1H), 3.96-4.10 (2H), 4.29-4.48 (3H), 7.17 (1H),7.36-7.50 (5H), 8.52 (1H), 8.75-8.82 (1H).

Example 742-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-6-methyl-N-(2-morpholinoethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 30 mg of the title compound was obtained from79 mg of the amine prepared in Example 74a and 26 mg of 4-chlorobenzoylchloride.

¹NMR (400 MHz, methanol-d₄): δ [ppm], 1.31 (2H), 1.50 (1H), 1.65 (1H),2.35 (1H), 2.47 (3H), 2.63 (6H), 2.81 (1H), 3.07 (1H), 3.53 (2H), 3.71(5H), 4.34 (2H), 4.59 (1H), 7.36 (2H), 7.43 (3H), 7.75 (1H), 8.24 (1H).

The starting material was prepared as follows:

Example 74a6-methyl-N-(2-morpholinoethyl)-2-(4-piperidylmethyl)-2H-indazol-5-carboxamide

768 mg of (1.58 mmol) of tert-butyl carbamate 74b were dissolved in 4.0ml 4M hydrochloric acid in dioxan and stirred under nitrogen at roomtemperature. A further 0.8 ml 4M hydrochloric acid in dioxan were addedand the mixture stirred at room temperature. The reaction solution wasconcentrated and yielded 760 mg of the title compound, which was used inthe next reaction without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.34-1.50 (2H), 1.53-1.67 (2H),2.21-2.30 (1H), 2.41 (3H), 2.74-2.89 (2H), 3.07-3.33 (8H), 3.62-3.71(2H), 3.77-3.90 (2H), 3.90-4.03 (2H), 4.35 (2H), 7.39 (1H), 7.88 (1H),8.44 (1H), 8.57 (1H), 8.62-8.79 (1H), 8.87-9.02 (1H), 11.17 (1H).

Example 74b Tert-butyl4-({6-methyl-5-[N-(2-morpholinoethyl)carbamoyl]-2H-indazol-2-yl}-methyl)piperidin-1-carboxylate

3.00 g (7.35 mmol) of 5-bromoindazole 74c and 2.87 g (22.04 mmol) of2-morpholinoethylamine were dissolved in 134 ml dioxan and 1.94 g (7.35mmol) of molybdenum hexacarbonyl, 167 mg (1.47 mmol) of palladiumacetate, 213 mg (0.74 mmol) of tributylphosphonium tetrafluoroborate,2.34 g (22.0 mmol) of sodium carbonate and 2 drops of water were added.The reaction mixture was heated to 125° C. under nitrogen and stirred atthis temperature for 2.5 hrs. For the work-up, the suspension wasfiltered over Celite, rewashed with dioxan, concentrated in vacuo anddried. The crude product was separated by column chromatography. Yield:518 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.93-1.16 (2H), 1.26-1.37 (2H), 1.34(9H), 1.99-2.17 (1H), 2.32-2.43 (10H), 2.54-2.72 (2H), 3.34 (1H),3.48-3.59 (4H), 3.86 (2H), 4.26 (2H), 7.35 (1H), 7.63 (1H), 8.09 (1H),8.32 (1H).

Example 74c Tert-butyl4-[(5-bromo-6-methyl-2H-indazol-2-yl)methyl]piperidin-1-carboxylate

10.0 g (47.4 mmol) of 5-bromo-4-methyl-1H-indazole and 21.0 g (56.9mmol) of tert-butyl 4-[(tosyloxy)methyl]piperidin-1-carboxylate weredissolved in 726 ml DMF. To this were added 21.0 g (56.9 mmol) oftetrabutylammonium iodide and 18.5 g (56.9 mmol) of caesium carbonateand the reaction mixture was heated under nitrogen at 80° C. for 1.5hrs. For the work-up, it was treated with water and ethyl acetate, theorganic phase separated and the aqueous phase extracted several timeswith ethyl acetate. The organic phases were washed with saturated sodiumchloride solution, dried over sodium sulphate and concentrated in vacuo.After purification by column chromatography, this yielded the titlecompound in 5 g yield.

¹H-NMR (600 MHz, chloroform-d): δ [ppm], 1.16-1.30 (2H), 1.45 (9H), 1.54(2H), 2.22-2.33 (1H), 2.51 (3H), 2.67 (2H), 4.03-4.17 (2H), 4.27-4.32(2H), 7.60 (1H), 7.81 (1H), 7.90 (1H).

The following compounds were prepared analogously:

Ex. Structure IUPAC name Analysis 75

6-methyl-N-(2- morpholinoethyl)-2- ({1-[4-(trifluorometh-oxy)benzoyl]piperidin- 4-yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR(400 MHz, methanol- d₄): δ [ppm] = 1.32 (2H), 1.51 (1H), 1.65 (1H), 2.36(1H), 2.47 (3H), 2.60 (6H), 2.83 (1H), 3.10 (1H), 3.52 (2H), 3.70 (5H),4.35 (2H), 4.61 (1H), 7.37 (3H), 7.49 (2H), 7.74 (1H), 8.24 (1H). 76

6-methyl-N-(2- morpholinoethyl)-2- ({1-[3-(trifluorometh-oxy)benzoyl]piperidin- 4-yl}methyl)-2H- indazole-5- carboxamide ¹H-NMR(400 MHz, methanol- d₄): δ [ppm] = 1.32 (2H), 1.49 (1H), 1.65 (1H), 2.36(1H), 2.46 (3H), 2.59 (6H), 2.83 (1H), 3.10 (1H), 3.51 (2H), 3.69 (5H),4.35 (2H), 4.60 (1H), 7.33 (2H), 7.40 (2H), 7.54 (1H), 7.74 (1H), 8.24(1H).

Example 776-methyl-N-(2-morpholinoethyl)-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 23 mg of the title compound was obtained from79 mg of the amine prepared in Example 74a and 47 mg of the acid.

¹H-NMR (400 MHz, methanol-d4): δ [ppm], 1.34 (2H), 1.52 (1H), 1.66 (1H),2.37 (1H), 2.49 (3H), 2.84 (1H), 3.10 (1H), 3.25 (2H), 3.42 (2H), 3.63(3H), 3.75 (4H), 4.10 (2H), 4.36 (2H), 4.62 (1H), 7.43 (1H), 7.56 (2H),7.89 (3H), 8.28 (1H).

The following compounds were prepared analogously:

Ex. Structure IUPAC name Analysis 78

2-({1-[4-(4-fluoro- phenoxy)benzoyl]- piperidin-4-yl}-methyl)-6-methyl-N- (2-morpholinoethyl)- 2H-indazole-5- carboxamide¹H-NMR (400 MHz, methanol- d₄): δ [ppm] = 1.31 (2H), 1.58 (2H), 2.35(1H), 2.49 (3H), 2.40- 4.20 (15H), 4.35 (2H), 4.58 (1H), 6.97 (2H), 7.04(2H), 7.11 (2H), 7.37 (2H), 7.43 (1H), 7.87 (1H), 8.27 (1H). 79

6-methyl-N-(2- morpholinoethyl)-2- ({1-[4-(trifluoro- methyl)benzoyl]-piperidin-4-yl}- methyl)-2H-indazole- 5-carboxamide ¹H-NMR (300 MHz,methanol- d₄): δ [ppm] = 1.34 (2H), 1.51 (1H), 1.67 (1H), 2.38 (1H),2.50 (3H), 2.85 (1H), 3.10 (1H), 3.25 (2H), 3.43 (2H), 3.64 (3H), 3.76(4H), 4.10 (2H), 4.38 (2H), 4.64 (1H), 7.44 (1H), 7.57 (2H), 7.76 (2H),7.89 (1H), 8.31 (1H). 80

2-({1-[2-fluoro-4- (trifluoromethyl)benzoyl] piperidin-4-yl}-methyl)-6-methyl-N- (2-morpholinoethyl)- 2H-indazole-5- carboxamide¹H-NMR (300 MHz, methanol- d₄): δ [ppm] = 1.34 (2H), 1.54 (1H), 1.68(1H), 2.38 (1H), 2.50 (3H), 2.86 (1H), 3.12 (1H), 3.26 (2H), 3.43 (3H),3.66 (2H), 3.76 (4H), 4.11 (2H), 4.37 (2H), 4.67 (1H), 7.44 (1H), 7.59(3H), 7.89 (1H), 8.31 (1H). 81

6-methyl-N-(2- morpholinoethyl)-2- ({1-[3-(pentafluoro-λ⁶-sulphanyl)benzoyl]- piperidin-4-yl}- methyl)-2H-indazole- 5-carboxamide¹H-NMR (300 MHz, methanol- d₄): δ [ppm] = 1.35 (2H), 1.53 (1H), 1.65(1H), 2.38 (1H), 2.50 (3H), 2.86 (1H), 3.14 (1H), 3.26 (2H), 3.43 (2H),3.66 (3H), 3.76 (4H), 4.11 (2H), 4.37 (2H), 4.62 (1H), 7.44 (1H), 7.63(2H), 7.89 (3H), 8.30 (1H). 82

6-methyl-N-(2-morph- olinoethyl)-2-({1-[3- (trifluoromethyl)-benzoyl]piperidin-4- yl}methyl)-2H-indazole-5- carboxamide ¹H-NMR (300MHz, methanol- d₄): δ [ppm] = 1.35 (2H), 1.53 (1H), 1.65 (1H), 2.38(1H), 2.50 (3H), 2.85 (1H), 3.12 (1H), 3.26 (2H), 3.43 (2H), 3.66 (3H),3.76 (4H), 4.11 (2H), 4.38 (2H), 4.63 (1H), 7.45 (1H), 7.66 (3H), 7.77(1H), 7.90 (1H), 8.33 (1H). 83

2-({1-[(4′-fluoro- biphenyl-4-yl)- carbonyl]piperidin-4-yl}methyl)-6-methyl- N-(2-morpholino- ethyl)-2H-indazole-5- carboxamide¹H-NMR (300 MHz, methanol- d₄): δ [ppm] = 1.35 (2H), 1.53 (1H), 1.65(1H), 2.39 (1H), 2.50 (3H), 2.85 (1H), 3.12 (1H), 3.26 (2H), 3.42 (2H),3.63 (3H), 3.74 (4H), 4.08 (2H), 4.37 (2H), 4.64 (1H), 7.18 (2H), 7.46(3H), 7.66 (4H), 7.88 (1H), 8.30 (1H).

Example 842-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 38 mg of the title compound was obtained from75 mg of the amine prepared in Example 84a and 29 mg of 4-chlorobenzoicacid.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 0.14 (2H), 0.42 (2H), 0.97 (1H),1.21 (2H), 1.36 (1H), 1.52 (1H), 2.27 (1H), 2.50 (3H), 2.72 (1H), 2.97(1H), 3.23 (2H), 3.36 (2H), 3.48 (3H), 4.31 (2H), 4.40 (1H), 7.14 (1H),7.36 (3H), 7.46 (2H), 8.12 (1H), 8.47 (1H).

The starting material was prepared as follows:

Example 84aN-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamide

To 781 mg of 84b were added 3.7 ml of 4M hydrochloric acid in dioxan and0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30° C. Thereaction mixture was concentrated, taken up in some toluene and againconcentrated. Yield: 751 mg of the title compound, which was furtherreacted without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 0.14 (2H), 0.42 (2H), 0.97 (1H),1.43 (2H), 1.58 (2H), 2.26 (1H), 2.50 (3H), 2.65 (1H), 2.78 (2H), 3.18(2H), 3.22 (2H), 3.36 (2H), 3.49 (2H), 4.33 (2H), 7.16 (2H), 7.38 (1H),8.11 (1H), 8.53 (1H), 8.80 (1H), 9.06 (1H).

Example 84b Tert-butyl4-[(5-{N-[2-(cyclopropylmethoxy)ethyl]carbamoyl}-4-methyl-2H-indazol-2-yl)methyl]piperidin-1-carboxylate

500 mg of 1d was reacted with 203 mg of amine analogously to 1b versionB. Yield: 781 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.98-1.13 (2H), 1.34 (11H),2.05-2.27 (2H), 2.33-2.41 (5H), 2.51 (3H), 2.56-2.73 (2H), 3.25-3.37(2H), 3.51-3.57 (4H), 3.81-3.93 (2H), 4.28 (2H), 7.14 (1H), 7.36-7.41(1H), 7.95-8.02 (1H), 8.46 (1H).

The following compounds were prepared analogously:

Ex. Structure IUPAC name Analysis 85

N-[2-(cyclopropyl- methoxy)ethyl]-4- methyl-2-{[1-(4- methylbenzoyl)-piperidin-4-yl]- methyl}-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.14 (2H), 0.42 (2H), 0.97 (1H), 1.19 (2H), 1.37(1H), 1.50 (1H), 2.26 (1H), 2.29 (3H), 2.50 (3H), 2.72 (1H), 2.94 (1H),3.23 (2H), 3.36 (2H), 3.48 (2H), 3.57 (1H), 4.30 (2H), 4.39 (1H), 7.14(1H), 7.21 (4H), 7.38 (1H), 8.12 (1H), 8.47 (1H). 86

N-[2-(cyclopropyl- methoxy)ethyl]-2-({1- [4-(4-fluorophenoxy)-benzoyl]piperidin-4- yl}methyl)-4-methyl- 2H-indazole-5- carboxamide¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.14 (2H), 0.42 (2H), 0.97 (1H),1.19 (2H), 1.45 (2H), 2.26 (1H), 2.50 (3H), 2.75 (1H), 2.96 (1H), 3.23(2H), 3.36 (2H), 3.48 (2H), 3.62 (1H), 4.31 (2H), 4.39 (1H), 6.95 (2H),7.12 (3H), 7.23 (2H), 7.36 (3H), 8.12 (1H), 8.47 (1H). 87

N-[2-(cyclopropyl- methoxy)ethyl]-4- methyl-2-({1-[4-(tri-fluoromethyl)benzoyl] piperidin-4-yl}- methyl)-2H-indazole-5-carboxamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.14 (2H), 0.42 (2H),0.96 (1H), 1.22 (2H), 1.36 (1H), 1.56 (1H), 2.28 (1H), 2.50 (3H), 2.74(1H), 2.99 (1H), 3.23 (2H), 3.36 (2H), 2.43 (1H), 3.48 (2H), 4.31 (2H),4.43 (1H), 7.15 (1H), 7.38 (1H), 7.55 (2H), 7.77 (2H), 8.12 (1H), 8.47(1H). 88

N-[2-(cyclopropyl- methoxy)ethyl]-2-({1- [(4′-fluorobiphenyl-4-yl)carbonyl]piperidin- 4-yl}methyl)-5- methyl-2H-indazole-5- carboxamide¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.14 (2H), 0.42 (2H), 0.96 (1H),1.23 (2H), 1.39 (1H), 1.55 (1H), 2.28 (1H), 2.50 (3H), 2.74 (1H), 3.01(1H), 3.23 (2H), 3.36 (2H), 3.48 (2H), 3.61 (1H), 4.33 (2H), 4.44 (1H),7.15 (1H), 7.28 (2H), 7.40 (3H), 7.69 (4H), 8.12 (1H), 8.48 (1H). 89

2-{[1-(4-cyclopropyl- benzoyl)piperidin-4- yl]methyl}-N-[2-(cyclopropylmethoxy) ethyl]-4-methyl-2H- indazole-5- carboxamide ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.17 (2H), 0.45 (2H), 0.69 (2H), 0.97(3H), 1.21 (2H), 1.47 (2H), 1.93 (1H), 2.27 (1H), 2.52 (3H), 2.78 (1H),2.93 (1H), 3.26 (2H), 3.37 (2H), 3.51 (2H), 3.62 (1H), 4.34 (2H), 4.41(1H), 7.10 (2H), 7.17 (1H), 7.22 (2H), 7.41 (1H), 8.11 (1H), 8.49 (1H).

Example 902-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoro-ethoxy)ethyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 40 mg of the title compound was obtained from75 mg of the amine prepared in Example 90a and 27 mg of 4-chlorobenzoicacid.

¹H-NMR (400 MHz, DMSO-d₆): □ [ppm], 1.20 (2H), 1.36 (1H), 1.53 (1H),2.27 (1H), 2.49 (3H), 2.72 (1H), 2.97 (1H), 3.40 (2H), 3.49 (1H), 3.69(2H), 4.07 (2H), 4.31 (2H), 4.40 (1H), 7.15 (1H), 7.37 (3H), 7.46 (2H),8.19 (1H), 8.48 (1H).

The starting material was prepared as follows:

Example 90a4-methyl-2-(4-piperidylmethyl)-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide

To 610 mg of 90b were added 3.0 ml of 4M hydrochloric acid in dioxan and0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30° C. Thereaction mixture was concentrated, taken up in some toluene and againconcentrated. Yield: 619 mg of the title compound, which was furtherreacted without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.42 (2H), 1.59 (2H), 2.26 (1H),2.50 (3H), 2.64 (1H), 2.79 (2H), 3.20 (2H), 3.40 (2H), 3.70 (2H), 4.07(2H), 4.33 (2H), 5.67 (1H), 7.16 (1H), 7.39 (1H), 8.18 (1H), 8.53 (1H),8.69 (1H), 8.94 (1H).

Example 90b Tert-butyl4-[(4-methyl-5-{N-[2-(2,2,2-trifluoroethoxy)ethyl]carbamoyl}-2H-indazol-2-yl)methyl]piperidin-1-carboxylate

500 mg of 1d was reacted with 240 mg of amine analogously to 1b versionB. Yield: 670 mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.07 (2H), 1.34 (9H), 1.37 (2H),2.14 (1H), 2.49 (3H), 2.63 (2H), 3.40 (2H), 3.70 (2H), 3.88 (2H), 4.06(2H), 4.29 (2H), 7.15 (1H), 7.39 (1H), 8.16 (1H), 8.47 (1H).

The following compounds were prepared analogously:

Ex. Structure IUPAC name Analysis 91

4-methyl-2-{[1-(4- methylbenzoyl)- piperidin-4-yl]- methyl}-N-[2-(2,2,2-trifluoro- ethoxy)ethyl]-2H- indazole-5- carboxamide ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 1.19 (2H), 1.36 (1H), 1.49 (1H), 2.25 (1H),2.29 (3H), 2.49 (3H), 2.71 (1H), 2.93 (1H), 3.40 (2H), 3.56 (1H), 3.69(2H), 4.07 (2H), 4.31 (2H), 4.40 (1H), 7.15 (1H), 7.21 (4H), 7.39 (1H),8.19 (1H), 8.48 (1H). 92

2-({1-[4-(4-fluoro- phenoxy)benzoyl]- piperidin-4-yl}- methyl)-4-methyl-N-[2-(2,2,2-tri- fluoroethoxy)ethyl]- 2H-indazole-5- carboxamide ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 1.19 (2H), 1.44 (2H), 2.26 (1H), 2.49(3H), 2.73 (1H), 2.95 (1H), 3.40 (2H), 3.60 (1H), 3.69 (2H), 4.07 (2H),4.31 (2H), 4.38 (1H), 6.95 (2H), 7.12 (3H), 7.22 (2H), 7.37 (3H), 8.19(1H), 8.48 (1H). 93

4-methyl-N-[2- (2,2,2-trifluoro- ethoxy)ethyl]-2-({1- [4-(trifluoro-methyl)benzoyl]- piperidin-4-yl}- methyl)-2H- indazole-5- carboxamide¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.22 (2H), 1.36 (1H), 1.56 (1H),2.28 (1H), 2.49 (3H), 2.74 (1H), 2.99 (1H), 3.40 (3H), 3.69 (2H), 4.07(2H), 4.32 (2H), 4.43 (1H), 7.15 (1H), 7.39 (1H), 7.55 (2H), 7.77 (2H),8.19 (1H), 8.48 (1H). 94

2-({1-[(4′-fluoro- biphenyl-4-yl)- carbonyl]piperidin- 4-yl}methyl)-4-methyl-N-[2-(2,2,2- trifluoroethoxy)- ethyl]-2H-indazole- 5-carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.23 (2H), 1.39 (1H), 1.52 (1H),2.28 (1H), 2.49 (3H), 2.75 (1H), 3.00 (1H), 3.39 (2H), 3.60 (1H), 3.69(2H), 4.07 (2H), 4.33 (2H), 4.43 (1H), 7.15 (1H), 7.27 (2H), 7.40 (3H),7.68 (4H), 8.19 (1H), 8.49 (1H). 95

2-{[1-(4-cyclo- propylbenzoyl)- piperidin-4-yl]- methyl}-4-methyl-N-[2-(2,2,2-tri- fluoroethoxy)ethyl]- 2H-indazole-5- carboxamide ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.69 (2H), 0.96 (2H), 1.21 (2H), 1.47(2H), 1.93 (1H), 2.28 (1H), 2.52 (3H), 2.77 (1H), 2.94 (1H), 3.43 (2H),3.61 (1H), 3.72 (2H), 4.09 (2H), 4.34 (2H), 4.42 (1H), 7.10 (2H), 7.17(1H), 7.22 (2H), 7.41 (1H), 8.18 (1H).

Example 962-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 36 mg of the title compound was obtained from75 mg of the amine prepared in Example 96a and 30 mg of 4-chlorobenzoicacid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.07 (6H), 1.22 (2H), 1.39 (1H),1.51 (1H), 2.26 (1H), 2.50 (3H), 2.75 (1H), 2.97 (1H), 3.33 (2H), 3.45(3H), 3.55 (1H), 4.31 (2H), 4.39 (1H), 7.14 (1H), 7.36 (3H), 7.47 (2H),8.05 (1H), 8.46 (1H).

The starting material was prepared as follows:

Example 96aN-(2-isopropoxyethyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazol-5-carboxamide

To 650 mg of 96b were added 3.2 ml of 4M hydrochloric acid in dioxan and0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30° C. Thereaction mixture was concentrated, taken up in some toluene and againconcentrated. Yield: 529 mg of the title compound, which was furtherreacted without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.06 (3H), 1.07 (3H), 1.42 (2H),1.57 (2H), 2.25 (1H), 2.50 (3H), 2.65 (1H), 2.78 (2H), 3.19 (2H), 3.32(2H), 3.45 (2H), 3.55 (1H), 4.32 (1H), 6.61 (1H), 7.15 (1H), 7.38 (1H),8.11 (1H), 8.53 (1H), 8.78 (1H), 9.04 (1H).

Example 96b Tert-butyl4-({5-[N-(2-isopropoxyethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)piperidin-1-carboxylate

500 mg of 1d was reacted with 138 mg of amine analogously to 1b versionB. Yield: 650 mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.07 (8H), 1.34 (9H), 1.38 (2H), 2.13(1H), 2.50 (3H), 2.63 (2H), 3.33 (2H), 3.46 (2H), 3.55 (1H), 3.87 (2H),4.28 (2H), 7.14 (1H), 7.38 (1H), 8.05 (1H), 8.46 (1H).

The following compounds were prepared analogously:

Ex. Structure IUPAC name Analysis  97

N-(2-isopropoxy- ethyl)-4-methyl-2- {[1-(4-methyl- benzoyl)piperidin-4-yl]methyl}-2H- indazole-5- carboxamide ¹H-NMR (300 MHz, DMSO-d₆): δ[ppm] = 1.07 (6H), 1.19 (2H), 1.45 (2H), 2.29 (4H), 2.50 (3H), 2.75(1H), 2.92 (1H), 3.33 (2H), 3.45 (2H), 3.55 (2H), 4.31 (2H), 4.40 (1H),7.14 (1H), 7.20 (4H), 7.38 (1H), 8.05 (1H), 8.46 (1H).  98

2-({1-[4-(4-fluoro- phenoxy)benzoyl]- piperidin-4-yl}- methyl)-N-(2-isopropoxyethyl)-4- methyl-2H-indazole- 5-carboxamide ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm] = 1.07 (6H), 1.21 (2H), 1.45 (2H), 2.25 (1H), 2.49(3H), 2.85 (2H), 3.31 (2H), 3.45 (2H), 3.55 (2H), 4.31 (2H), 4.40 (1H),6.95 (2H), 7.10 (3H), 7.22 (2H), 7.36 (3H), 8.05 (1H), 8.46 (1H).  99

N-(2-isopropoxy- ethyl)-4-methyl-2- ({1-[4-(trifluoro- methyl)benzoyl]-piperidin-4-yl}- methyl)-2H-indazole- 5-carboxamide ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm] = 1.06 (6H), 1.22 (2H), 1.37 (1H), 1.56 (1H), 2.28(1H), 2.50 (3H), 2.75 (1H), 2.99 (1H), 3.33 (2H), 3.45 (3H), 3.55 (1H),4.32 (2H), 4.43 (1H), 7.15 (1H), 7.38 (1H), 7.55 (2H), 7.77 (2H), 8.05(1H), 8.46 (1H). 100

2-({1-[(4′-fluoro- biphenyl-4-yl)- carbonyl]piperidin-4-yl}methyl)-N-(2- isopropoxyethyl)-4- methyl-2H-indazole- 5-carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.06 (6H), 1.23 (2H), 1.47 (2H),2.28 (1H), 2.50 (3H), 2.76 (1H), 2.98 (1H), 3.33 (2H), 3.45 (2H), 3.55(2H), 4.33 (2H), 4.43 (1H), 7.15 (1H), 7.27 (2H), 7.39 (3H), 7.68 (4H),8.05 (1H), 8.47 (1H). 101

2-{[1-(4-cyclopropyl- benzoyl)piperidin-4- yl]methyl}-N-(2-isopropoxyethyl)-4- methyl-2H-indazole- 5-carboxamide ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm] = 0.66 (2H), 0.94 (2H), 1.06 (6H), 1.20 (2H), 1.44(2H), 1.90 (1H), 2.24 (1H),2.49 (3H), 2.82 (2H), 3.32 (2H), 3.45 (2H),3.55 (2H), 4.31 (2H), 4.39 (1H), 7.12 (5H), 7.38 (1H), 8.05 (1H), 8.46(1H).

Example 102(+/−)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)propyl]-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 41 mg of the title compound was obtained from100 mg of the amine prepared in Example 102a and 37 mg of4-chlorobenzoic acid.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 0.16 (2H), 0.43 (2H), 0.97 (1H),1.10 (3H), 1.23 (2H), 1.40 (1H), 1.55 (1H), 2.29 (1H), 2.53 (3H), 2.75(1H), 2.99 (1H), 3.23 (2H), 3.20 (2H), 3.51 (1H), 3.59 (1H), 4.34 (2H),4.43 (1H), 7.17 (1H), 7.39 (3H), 7.49 (2H), 8.09 (1H), 8.49 (1H).

The starting material was prepared as follows:

Example 102a(+/−)-N-[2-(cyclopropylmethoxy)propyl]-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamide

To 632 mg of 102b were added 2.9 ml of 4M hydrochloric acid in dioxanand 0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30° C. Thereaction mixture was concentrated, taken up in some toluene and againconcentrated. Yield: 561 mg of the title compound, which was furtherreacted without further purification.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.13 (2H), 0.40 (2H), 0.94 (1H),1.07 (3H), 1.44 (2H), 1.57 (2H), 2.26 (1H), 2.50 (3H), 2.77 (2H), 3.20(6H), 3.57 (1H), 4.33 (2H), 6.33 (1H), 7.16 (1H), 7.39 (1H), 8.11 (1H),8.53 (1H), 8.79 (1H), 9.06 (1H).

Example 102b (+/−)-tert-butyl4-[(5-{N-[2-(cyclopropylmethoxy)propyl]carbamoyl}-4-methyl-2H-indazol-2-yl)methyl]piperidin-1-carboxylate

500 mg of 1d was reacted with 222 mg of amine analogously to 1b versionB. Yield: 631 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.13 (2H), 0.40 (2H), 0-94 (1H),1.07 (3H), 1.14 (2H), 1.34 (9H), 1.38 (2H), 2.13 (1H), 2.50 (3H), 3.24(6H), 3.57 (1H), 3.87 (2H), 4.28 (2H), 7.15 (1H), 7.39 (1H), 8.09 (1H),8.46 (1H).

The following compounds were prepared analogously:

Ex. Structure IUPAC name Analysis 103

(+/−)-N-[2-(cyclo- propylmethoxy)- propyl]-2-({1-[4-(4- fluorophenoxy)-benzoyl]piperidin-4- yl}methyl)-4-methyl- 2H-indazole-5- carboxamide¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.16 (2H), 0.43 (2H), 0.97 (1H),1.10 (3H), 1.22 (2H), 1.48 (2H), 2.29 (1H), 2.53 (3H), 2.81 (1H), 2.92(1H), 3.23 (2H), 3.28 (2H), 3.60 (1H), 3.70 (1H), 4.34 (2H), 4.42 (1H),6.98 (2H), 7.14 (3H), 7.25 (2H), 7.39 (3H), 8.09 (1H), 8.49 (1H). 104

(+/−)-N-[2-(cyclo- propylmethoxy)- propyl]-4-methyl-2-({1-[4-(trifluoro- methyl)benzoyl]- piperidin-4-yl}-methyl)-2H-indazole- 5-carboxamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.16 (2H), 0.43 (2H), 0.97 (1H), 1.10 (3H), 1.24 (2H), 1.38 (1H), 1.59(1H), 2.30 (1H), 2.53 (3H), 2.78 (1H), 3.02 (1H), 3.23 (2H), 3.28 (2H),3.45 (1H), 3.60 (1H), 4.34 (2H), 4.46 (1H), 7.17 (1H), 7.41 (1H), 7.57(2H), 7.80 (2H), 8.09 (1H), 8.49 (1H). 105

(+/−)-N-[2-(cyclo- propylmethoxy)- propyl]-2-({1-[(4′- fluorobiphenyl-4-yl)carbonyl]- piperidin-4-yl}- methyl)-4-methyl- 2H-indazole-5-carboxamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.16 (2H), 0.42 (2H),0.97 (1H), 1.10 (3H), 1.26 (2H), 1.45 (1H), 1.55 (1H), 2.32 (1H), 2.53(3H), 2.79 (1H), 3.03 (1H), 3.23 (2H), 3.27 (2H), 3.60 (2H), 4.36 (2H),4.46 (1H), 7.17 (1H), 7.30 (2H), 7.42 (3H), 7.71 (4H), 8.09 (1H), 8.50(1H). 106

(+/−)-2-{[1-(4- cyclopropylbenzoyl) piperidin-4-yl]- methyl}-N-[2-(cyclopropyl- methoxy)propyl]-4- methyl-2H-indazole- 5-carboxamide¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.16 (2H), 0.43 (2H), 0.69 (2H),0.96 (3H), 1.10 (3H), 1.20 (2H), 1.47 (2H), 1.93 (1H), 2.28 (1H), 2.53(3H), 2.77 (1H), 2.93 (1H), 3.23 (2H), 3.28 (2H), 3.59 (2H), 4.34 (2H),4.40 (1H), 7.10 (2H), 7.17 (1H), 7.22 (2H), 7.41 (1H), 8.09 (1H), 8.49(1H).

Example 1072-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 26 mg of the title compound was obtained from75 mg of the amine prepared in Example 107a and 28 mg of 4-chlorobenzoicacid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.20 (2H), 1.36 (1H), 1.52 (1H),2.27 (1H), 2.49 (3H), 2.72 (1H), 2.97 (1H), 3.51 (3H), 4.17 (2H), 4.33(3H), 7.15 (1H), 7.41 (5H), 8.37 (1H), 8.49 (1H).

The starting material was prepared as follows:

Example 107a4-methyl-2-(4-piperidylmethyl)-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide

To 648 mg of 107b were added 3.0 ml of 4M hydrochloric acid in dioxanand 0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30° C. Thereaction mixture was concentrated, taken up in some toluene and againconcentrated. Yield: 766 mg of the title compound, which was furtherreacted without further purification.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.43 (2H), 1.57 (2H), 2.24 (1H),2.50 (3H), 2.78 (2H), 3.19 (2H), 3.50 (1H), 4.17 (2H), 4.33 (2H), 6.49(1H), 7.17 (2H), 7.40 (1H), 8.39 (1H), 8.55 (1H), 8.70 (1H), 8.98 (1H).

Example 107b Tert-butyl4-[(4-methyl-5-{N-[2-(trifluoromethoxy)ethyl]carbamoyl}-2H-indazol-2-yl)methyl]piperidin-1-carboxylate

500 mg of 1d was reacted with 293 mg of amine analogously to 1b versionB. Yield: 748 mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.07 (2H), 1.34 (9H), 1.37 (2H),2.12 (1H), 2.50 (3H), 2.63 (1H), 3.52 (2H), 3.87 (2H), 4.17 (2H), 4.29(2H), 7.16 (2H), 7.41 (1H), 8.37 (1H), 8.48 (1H).

The following compounds were prepared analogously:

Ex. Structure IUPAC name Analysis 108

2-({1-[4-(4-fluoro- phenoxy)benzoyl]- piperidin-4-yl}methyl)-4-methyl-N-[2-(tri- fluoromethoxy)ethyl]- 2H-indazole-5- carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.19 (2H), 1.46 (2H), 2.26 (1H),2.49 (3H), 2.87 (2H), 3.51 (3H), 4.17 (2H), 4.33 (3H), 6.95 (2H), 7.16(5H), 7.38 (3H), 8.36 (1H), 8.49 (1H). 109

2-({1-[(4′-fluoro- biphenyl-4-yl)- carbonyl]piperidin-4-yl}methyl)-4-methyl-N- [2-(trifluoro- methoxy)ethyl]-2H-indazole-5-carboxamide ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.23 (2H),1.47 (2H), 2.28 (1H), 2.50 (3H), 2.74 (1H), 2.99 (1H), 3.51 (2H), 3.61(1H), 4.17 (2H), 4.34 (3H), 7.16 (1H), 7.27 (2H), 7.40 (3H), 7.68 (4H),8.37 (1H), 8.50 (1H). 110

4-methyl-N-[2- (trifluoromethoxy)ethyl]- 2-[(1-{4-[4-(trifluoro-methyl)phenoxy]- benzoyl}piperidin-4-yl)- methyl]-2H-indazole-5-carboxamide ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.21 (2H), 1.46 (2H),2.27 (1H), 2.50 (3H), 2.76 (1H), 2.98 (1H), 3.51 (2H), 3.61 (1H), 4.17(2H), 4.33 (2H), 4.43 (1H), 7.14 (5H), 7.41 (3H), 7.73 (2H), 8.37 (1H),8.49 (1H).

Example 111N-(2-tert-butoxyethyl)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 8 mg of the title compound was obtained from75 mg of the amine prepared in Example 111a and 28 mg of 4-chlorobenzoicacid.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.12 (9H), 1.21 (2H), 1.36 (1H),1.53 (1H), 2.27 (1H), 2.50 (3H), 2.72 (1H), 2.97 (1H), 3.29 (2H), 3.43(3H), 4.31 (2H), 4.40 (1H), 7.14 (1H), 7.36 (3H), 7.46 (2H), 8.04 (1H),8.46 (1H).

The starting material was prepared as follows:

Example 111aN-(2-tert-butoxyethyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazol-5-carboxamide

To 743 mg of 111b were added 3.5 ml of 4M hydrochloric acid in dioxanand 0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30° C. Thereaction mixture was concentrated, taken up in some toluene and againconcentrated. Yield: 677 mg of the title compound in a mixture withN-(2-hydroxyethyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamide,which was further reacted without further purification.

Example 111b Tert-butyl4-({5-[N-(2-tert-butoxyethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}methyl)piperidin-1-carboxylate

500 mg of 1d was reacted with 206 mg of amine analogously to 1b versionB. Yield: 743 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.06 (2H), 1.11 (9H), 1.34 (9H),1.39 (2H), 2.13 (1H), 2.50 (3H), 2.65 (2H), 3.27 (2H), 3.40 (2H), 3.87(2H), 4.28 (2H), 7.14 (1H), 7.38 (1H), 8.05 (1H), 8.46 (1H).

The following compounds were prepared analogously:

Ex. Structure IUPAC name Analysis 112

N-(2-tert-butoxyethyl)- 2-({1-[4-(4-fluoro- phenoxy)benzoyl]-piperidin-4-yl}methyl)- 4-methyl-2H-indazole- 5-carboxamide ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 1.12 (9H), 1.20 (2H), 1.44 (2H), 2.26 (1H),2.50 (3H), 2.76 (1H), 2.93 (1H), 3.30 (2H), 3.40 (2H), 3.57 (1H), 4.31(2H), 4.39 (1H), 6.95 (2H), 7.12 (3H), 7.23 (2H), 7.36 (3H), 8.04 (1H),8.46 (1H). 113

N-(2-tert-butoxyphenyl)- 2-({1-[(4′-fluoro- biphenyl-4-yl)-carbonyl]piperidin-4- yl}methyl)-4-methyl- 2H-indazole-5- carboxamide¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.11 (9H), 1.23 (2H), 1.40 (1H),1.54 (1H), 2.29 (1H), 2.50 (3H), 2.75 (1H), 3.00 (1H), 3.29 (2H), 3.40(2H), 3.65 (1H), 4.32 (2H), 4.43 (1H), 7.15 (1H), 7.28 (2H), 7.40 (3H),7.69 (4H), 8.05 (1H), 8.47 (1H). 114

N-(tert-butoxyethyl)- 4-methyl-2-[(1-{4-[4- (trifluoromethyl)-phenoxy]benzoyl}- piperidin-4-yl)methyl]- 2H-indazole-5- carboxamide¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.12 (9H), 1.21 (2H), 1.40 (1H),1.52 (1H), 2.27 (1H), 2.50 (3H), 2.75 (1H), 2.99 (1H), 3.28 (2H), 3.40(2H), 3.60 (1H), 4.32 (2H), 4.40 (1H), 7.15 (5H), 7.40 (3H), 7.73 (2H),8.04 (1H), 8.47 (1H).

Example 1152-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-[²H₃]methoxy[²H₄]ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 1 mg of the title compound was obtained from54 mg of the amine prepared in Example 115a and 22 mg of 4-chlorobenzoicacid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.20 (2H), 1.40 (1H), 1.51 (1H),2.27 (1H), 2.49 (3H), 2.75 (1H), 2.96 (1H), 3.50 (1H), 4.31 (2H), 4.40(1H), 7.15 (1H), 7.36 (3H), 7.47 (2H), 8.07 (1H), 8.46 (1H).

The starting material was prepared as follows:

Example 115a4-methyl-N-(2-[²H₃]methyloxy[²H₄]ethyl)-2-(4-piperidylmethyl)-2H-indazole-5-carboxamide

To 131 mg of 115b were added 0.7 ml of 4M hydrochloric acid in dioxanand 0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30° C. Thereaction mixture was concentrated, taken up in some toluene and againconcentrated. Yield: 108 mg of the title compound, which was furtherreacted without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.42 (2H), 1.58 (2H), 2.26 (1H),2.49 (3H), 2.78 (2H), 3.19 (2H), 4.33 (2H), 5.55 (1H), 7.16 (1H), 7.38(1H), 8.12 (1H), 8.53 (1H), 8.70 (1H), 8.97 (1H).

Example 115b Tert-butyl4-({4-methyl-5-[N-(2-[²H₃]methyloxy[²H]ethyl)carbamoyl]-2H-indazol-2-yl}methyl)piperidin-1-carboxylate

500 mg of 1d was reacted analogously to 1b version B with 110 mg ofamine prepared in 115c. Yield: 131 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.07 (2H), 1.34 (9H), 1.37 (2H),2.13 (1H), 2.49 (3H), 2.62 (2H), 3.88 (2H), 4.28 (2H), 7.15 (1H), 7.38(1H), 8.07 (1H), 8.46 (1H).

Example 115c 2-[²H₃]methyloxy[²H₄]ethan-1-amine

110 mg of (0.51 mmol) of 115d was first placed in 2.2 ml toluene. Afteraddition of 11 mg of palladium/charcoal (10%) and hydrogen under normalpressure, the mixture was stirred for 50 mins at room temperature. Thereaction mixture was filtered through Celite and rewashed with toluene.The colourless filtrate was used as solution in the subsequent reaction.

Example 115d Benzyl N-(2-[²H₃]methyloxy [²H₄]ethyl)carbamate

1.32 g (6.6 mmol) of 115e) was dissolved in 23 ml acetonitrile. 2.3 g(9.9 mmol) of silver oxide and 1.64 ml (3.8 g, 26 mmol) of deuteratediodomethane were then added. The reaction mixture was stirred for 1.5hrs at 40° C., 7.5 hrs at 72° C. and then overnight at room temperature.A further 2.3 g (9.9 mmol) of silver oxide was added and the mixturestirred for 1.5 hrs at 72° C. For the work-up, the black solid wasfiltered off at the pump and the clear filtrate concentrated. Theresidue was purified by column chromatography (hexane/ethyl acetate0-10%). Yield: 1.13 g of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 4.97 (2H), 7.31 (5H).

Example 115e Benzyl N-(2-hydroxy[²H₄]ethyl)carbamate

1.0 g (15 mmol) of deuterated aminoethanol was first dissolved in 29 mldichloromethane. Then 2.5 ml (1.8 g, 18 mmol) of triethylamine was addedand the reaction mixture cooled to 0° C. At this temperature 2.75 ml(3.34 g, 19.6 mmol) of benzyl chloroformate was now cautiously addeddropwise. After completion of the addition, the mixture was stirred for1 hr more with no ice-bath and in the process warmed up to RT. Thereaction mixture was diluted once with some dichloromethane and washedonce with saturated sodium chloride solution. The organic phase wasdried over sodium sulphate, filtered and concentrated. The crude productwas purified twice by column chromatography (dichloromethane/methanol0-10% and ethyl acetate). Yield: 1.32 g of the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 4.54 (1H), 4.97 (2H), 7.12 (1H),7.81 (5H).

The following compound was prepared analogously:

Ex. Structure IUPAC name Analysis 116

2-({1-[4-(4-fluoro- phenoxy)benzoyl]- piperidin-4-yl}methyl)-4-methyl-N-(2-[²H₃]- methyloxy[²H₄]ethyl)- 2H-indazole-5- carboxamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 1.19 (2H), 1.46 (2H), 2.25 (1H),2.49 (3H), 2.85 (2H), 3.66 (1H), 4.31 (2H), 4.38 (1H), 6.95 (2H), 7.16(5H), 7.36 (3H), 8.07 (1H), 8.46 (1H).

Example 1172-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 471 mg of the title compound was obtainedfrom 500 mg of the compound prepared in Example 117e) and 287 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d₆): δ=2.49 (3H), 3.22 (1H), 3.25 (3H), 3.32-3.46(4H), 3.89 (1H), 4.09 (1H), 4.19 (1H), 4.37 (1H), 4.67 (2H), 7.15 (1H),7.38 (1H), 7.48 (2H), 7.59 (2H), 8.12 (1H), 8.54 (1H).

The starting material was prepared as follows:

Example 117a Tert-butyl3-[(5-bromo-4-methyl-2H-indazol-2-yl)methyl]-azetidin-1-carboxylate

To a solution of 21.1 g of 5-bromo-4-methyl-1H-indazole and 37.6 g oftert-butyl-3-[(tosyloxy)-methyl]azetidin-1-carboxylate in 100 ml dioxanwere added 150 ml of a 1M solution of sodium bis(trimethylsilyl)amide intetrahydrofuran at 25° C. and this was stirred for 6 hrs at 90° C. Aftercooling, the reaction mixture was treated with ethyl acetate and water,the organic phases separated and the aqueous phase extracted twice with100 ml portions of ethyl acetate. The combined organic phases werewashed with saturated sodium chloride solution, dried over sodiumsulphate, and concentrated in vacuo after filtration. The residue thusobtained was purified by chromatography on the Flashmaster (hexane/ethylacetate 1:0-0:1). 15.0 g of the title compound was obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.32 (9H), 2.48 (3H), 3.07 (1H), 3.69 (2H),3.87 (2H), 4.59 (2H), 7.28 (1H), 7.35 (1H), 8.53 (1H).

Example 117b Methyl2-{[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}-4-methyl-2H-indazol-5-carboxylate

To a solution of 8.16 g of the bromide prepared in Example 117a in 65.4ml methanol, 6.5 g of 1,1 bis(diphenylphosphino)ferrocen-palladium(II)dichloride and 15 g of potassium acetate were added at 25° C. and themixture was stirred under CO at 10.15 bar and 120° C. for 24 hours in anautoclave. The reaction mixture was then cooled, filtered through Celiteat the pump and the filtrate concentrated in vacuo. The residue thusobtained was purified by chromatography on the Flashmaster (hexane/ethylacetate 1:0-0:1). 6.97 g of the title compound was obtained.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.73 (3H), 3.09 (1H), 3.71 (2H),3.79 (3H), 3.87 (2H), 4.62 (2H), 7.42 (1H), 7.63 (1H), 8.74 (1H).

Example 117c2-{[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}-4-methyl-2H-indazol-5-carboxylicacid

Analogously to Example 1d, 5.2 g of the title compound was obtained from15.1 g of the ester prepared in Example 117b.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.73 (3H), 3.09 (1H), 3.71 (2H),3.87 (2H), 4.61 (2H), 7.39 (1H), 7.64 (1H), 8.70 (1H), 12.57 (1H).

Example 117d Tert-butyl3-({5-[N-(2-methoxyethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)azetidin-1-carboxylate

Analogously to Example 1, from 2.5 g of the acid prepared in Example117c and 0.54 g of 2-methoxyethylamine, a crude product was obtainedwhich through purification with a Biotage unit (ethyl acetate: 0 to 30%methanol) yielded 2.69 g of the title compound.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.49 (3H), 3.08 (1H), 3.25 (3H),3.32-3.46 (4H), 3.70 (2H), 3.86 (2H), 4.60 (2H), 7.15 (1H), 7.38 (1H),8.11 (1H), 8.54 (1H).

Example 117e2-(azetidin-3-ylmethyl)-N-(2-methoxyethyl)-4-methyl-2H-indazol-5-carboxamidehydrochloride

Analogously to Example 1a, from 2.69 g of the amide prepared in Example117d, 2.59 g of the title compound was obtained, which was reactedwithout further purification.

Example 118N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 29 mg of the title compound was obtained from55 mg of the compound prepared in Example 117e and 43 mg of4-[(trifluoromethyl)sulphanyl]benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.22 (1H), 3.25 (3H), 3.36 (2H),3.42 (2H), 3.92 (1H), 4.11 (1H), 4.20 (1H), 4.39 (1H), 4.67 (2H), 7.15(1H), 7.38 (1H), 7.69 (2H), 7.76 (2H), 8.12 (1H), 8.54 (1H).

Example 119N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 27 mg of the title compound was obtained from55 mg of the compound prepared in Example 117e and 40 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.20 (1H), 3.24 (3H), 3.32-3.46(4H), 3.91 (1H), 4.10 (1H), 4.20 (1H), 4.39 (1H), 4.67 (2H), 7.15 (1H),7.35-7.44 (3H), 7.70 (2H), 8.12 (1H), 8.54 (1H).

Example 1202-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 17 mg of the title compound was obtained from55 mg of the compound prepared in Example 117e and 41 mg of2-fluoro-4-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.48 (3H), 3.23 (1H), 3.25 (3H), 3.36 (2H),3.42 (2H), 3.94 (2H), 4.11 (2H), 4.66 (2H), 7.15 (1H), 7.38 (1H), 7.64(2H), 7.79 (1H), 8.12 (1H), 8.54 (1H).

Example 1212-{[1-(4-chloro-2-fluorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 19 mg of the title compound was obtained from42 mg of the compound prepared in Example 117e and 26 mg of4-chloro-2-fluorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.48 (3H), 3.21 (1H), 3.24 (3H), 3.33-3.46(4H), 3.86-3.97 (2H), 4.08 (2H), 4.65 (2H), 7.15 (1H), 7.34 (1H), 7.37(1H), 7.44 (1H), 7.52 (1H), 8.12 (1H), 8.53 (1H).

Example 1222-({1-[3-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 15 mg of the title compound was obtained from42 mg of the compound prepared in Example 117e and 31 mg of3-fluoro-4-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.21 (1H), 3.25 (3H), 3.36 (2H),3.42 (2H), 3.93 (1H), 4.12 (1H), 4.22 (1H), 4.40 (1H), 4.67 (2H), 7.15(1H), 7.37 (1H), 7.57 (1H), 7.64 (1H), 7.85 (1H), 8.12 (1H), 8.54 (1H).

Example 1232-({1-[4-chloro-3-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 6 mg of the title compound was obtained from42 mg of the compound prepared in Example 117e and 33 mg of4-chloro-3-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.21 (1H), 3.25 (3H), 3.31-3.46(4H), 3.92 (1H), 4.11 (1H), 4.22 (1H), 4.41 (1H), 4.67 (2H), 7.15 (1H),7.37 (1H), 7.79 (1H), 7.86 (1H), 7.94 (1H), 8.12 (1H), 8.53 (1H).

Example 1242-{[1-(4-cyclopropylbenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 76 mg of the title compound was obtained from163 mg of the compound prepared in Example 117e and 78 mg of4-cyclopropylbenzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=0.71 (2H), 0.99 (2H), 1.95 (1H), 2.52 (3H),3.24 (1H), 3.34-3.41 (5H), 3.45 (2H), 3.90 (1H), 4.09 (1H), 4.20 (1H),4.38 (1H), 4.68 (2H), 7.12 (2H), 7.18 (1H), 7.41 (1H), 7.48 (2H), 8.12(1H), 8.57 (1H).

Example 125N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 478 mg of the title compound was obtained from1.20 g of the compound prepared in Example 117e and 850 mg of4-[4-(trifluoromethyl)phenoxy]benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.52 (3H), 3.25 (1H), 3.27 (3H), 3.39 (2H),3.45 (2H), 3.94 (1H), 4.12 (1H), 4.24 (1H), 4.42 (1H), 4.70 (2H), 7.14(2H), 7.18 (1H), 7.22 (2H), 7.41 (1H), 7.69 (2H), 7.77 (2H), 8.12 (1H),8.57 (1H).

Example 1262-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 38 mg of the title compound was obtained from43 mg of the compound prepared in Example 126a and 20 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.10-2.27 (3H), 2.49 (3H), 2.57 (2H), 2.72(2H), 2.91 (2H), 3.17-3.36 (2H), 3.89 (1H), 4.08 (1H), 4.19 (1H), 4.36(1H), 4.67 (2H), 7.14 (1H), 7.38 (1H), 7.48 (2H), 7.59 (2H), 8.05 (1H),8.54 (1H).

Example 126a2-(azetidin-3-ylmethyl)-N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-methyl-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 50 mg of the compound prepared inExample 126b, 43 mg of the title compound was obtained, which wasreacted without further purification.

Example 126b Tert-butyl3-[(5-{N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]carbamoyl}-4-methyl-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

Analogously to Example 1b, 71 mg of the title compound was obtained from70 mg of the compound prepared in Example 117a and 83 mg of2-(3,3-difluoropyrrolidin-1-yl)ethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.10-2.28 (2H), 2.50 (3H), 2.57(2H), 2.66-2.77 (2H), 2.84-2.98 (2H), 3.08 (1H), 3.23-3.36 (2H), 3.69(2H), 3.86 (2H), 4.60 (2H), 7.14 (1H), 7.39 (1H), 8.05 (1H), 8.55 (1H).

Example 1272-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 143 mg of the title compound was obtainedfrom 130 mg of the compound prepared in Example 127b and 61 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.51 (3H), 3.13-3.29 (3H), 3.50 (2H), 3.90(1H), 4.09 (1H), 4.19 (1H), 4.37 (1H), 4.67 (2H), 7.19 (1H), 7.40 (1H),7.48 (2H), 7.59 (2H), 8.38 (1H), 8.57 (1H).

The starting material was prepared as follows:

Example 127a Tert-butyl3-{[4-methyl-5-(N-{2-[(trifluoromethyl)sulphanyl]ethyl}carbamoyl)-indazol-2-yl]methyl}azetidin-1-carboxylate

Analogously to Example 1, 674 mg of the title compound was obtained from500 mg of the compound prepared in Example 117c.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.52 (3H), 3.08 (1H), 3.17 (2H),3.50 (2H), 3.69 (2H), 3.86 (2H), 4.61 (2H), 7.19 (1H), 7.41 (1H), 8.38(1H), 8.57 (1H).

Example 127b2-(azetidin-3-ylmethyl)-4-methyl-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 150 mg of the compound prepared inExample 127a, 130 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 1282-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-(2-morpholinoethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 30 mg of the title compound was obtained from50 mg of the compound prepared in Example 128b and 24 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34-2.45 (6H), 2.51 (3H), 3.22 (1H), 3.33(2H), 3.54 (4H), 3.89 (1H), 4.08 (1H), 4.19 (1H), 4.36 (1H), 4.67 (2H),7.15 (1H), 7.38 (1H), 7.48 (2H), 7.59 (2H), 7.99 (1H), 8.54 (1H).

The starting material was prepared as follows:

Example 128a Tert-butyl3-({4-methyl-5-[N-(2-morpholinoethyl)carbamoyl]-2H-indazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1b, 59 mg of the title compound was obtained from200 mg of the compound prepared in Example 117a and 205 mg of2-morpholinoethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.34-2.44 (6H), 2.52 (3H), 3.08(1H), 3.33 (2H), 3.54 (4H), 3.69 (2H), 3.86 (2H), 4.61 (2H), 7.15 (1H),7.39 (1H), 7.98 (1H), 8.55 (1H).

Example 128b2-(azetidin-3-ylmethyl)-4-methyl-N-(2-morpholinoethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 59 mg of the compound prepared inExample 128a, 63 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 1292-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 127 mg of the title compound was obtainedfrom 128 mg of the compound prepared in Example 129b and 68 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.50 (3H), 3.22 (1H), 3.90 (1H), 3.96-4.13(3H), 4.19 (1H), 4.37 (1H), 4.68 (2H), 7.18 (1H), 7.42 (1H), 7.48 (2H),7.59 (2H), 8.59 (1H), 8.79 (1H).

The starting material was prepared as follows:

Example 129a Tert-butyl3-({4-methyl-5-[N-(2,2,2-trifluoroethyl)carbamoyl]-2H-indazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1, 1.02 g of the title compound was obtained from1.0 g of the compound prepared in Example 117c and 287 mg of2,2,2-trifluoroethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.51 (3H), 3.09 (1H), 3.70 (2H),3.86 (2H), 4.03 (2H), 4.62 (2H), 7.17 (1H), 7.43 (1H), 8.60 (1H), 8.79(1H).

Example 129b2-(azetidin-3-ylmethyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 1.0 g of the compound prepared inExample 129a, 852 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 1304-methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 113 mg of the title compound was obtainedfrom 128 mg of the compound prepared in Example 129b and 87 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.50 (3H), 3.23 (1H), 3.92 (1H), 3.96-4.14(3H), 4.20 (1H), 4.39 (1H), 4.68 (2H), 7.18 (1H), 7.36-7.46 (3H), 7.70(2H), 8.59 (1H), 8.79 (1H).

Example 1312-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 128 mg of the title compound was obtainedfrom 128 mg of the compound prepared in Example 129b and 88 mg of2-fluoro-4-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.23 (1H), 3.89-4.16 (6H), 4.67(2H), 7.17 (1H), 7.42 (1H), 7.60-7.67 (2H), 7.79 (1H), 8.58 (1H), 8.80(1H).

Example 1324-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]azetidin-3-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 121 mg of the title compound was obtained from128 mg of the compound prepared in Example 129b and 96 mg of4-(pentafluoro-λ⁶-sufanyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.50 (3H), 3.24 (1H), 3.94 (1H), 3.98-4.08(2H), 4.12 (1H), 4.20 (1H), 4.39 (1H), 4.69 (2H), 7.18 (1H), 7.42 (1H),7.76 (2H), 7.95 (2H), 8.59 (1H), 8.80 (1H).

Example 1334-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 178 mg of the title compound was obtainedfrom 130 mg of the compound prepared in Example 127b and 78 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.51 (3H), 3.13-3.28 (3H), 3.51 (2H), 3.91(1H), 4.10 (1H), 4.20 (1H), 4.39 (1H), 4.67 (2H), 7.19 (1H), 7.40 (3H),7.70 (2H), 8.38 (1H), 8.57 (1H).

Example 1342-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 128 mg of the title compound was obtainedfrom 130 mg of the compound prepared in Example 127b and 79 mg of2-fluoro-4-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.51 (3H), 3.12-3.25 (3H), 3.50 (2H),3.89-3.98 (2H), 4.06-4.16 (2H), 4.67 (2H), 7.19 (1H), 7.40 (1H), 7.64(2H), 7.79 (1H), 8.39 (1H), 8.56 (1H).

Example 1354-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]azetidin-3-yl}methyl)-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 84 mg of the title compound was obtained from130 mg of the compound prepared in Example 127b and 87 mg of4-(pentafluoro-λ⁶-sulphanyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.51 (3H), 3.18 (2H), 3.23 (1H), 3.51 (2H),3.94 (1H), 4.12 (1H), 4.20 (1H), 4.39 (1H), 4.68 (2H), 7.19 (1H), 7.41(1H), 7.76 (2H), 7.95 (2H), 8.39 (1H), 8.56 (1H).

Example 136N-[2-(cyclopropyloxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 172 mg of the title compound was obtainedfrom 161 mg of the compound prepared in Example 136b and 109 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=0.36-0.48 (4H), 2.48 (3H), 3.22 (1H), 3.27(1H), 3.35 (2H), 3.53 (2H), 3.91 (1H), 4.10 (1H), 4.20 (1H), 4.39 (1H),4.67 (2H), 7.14 (1H), 7.35-7.44 (3H), 7.71 (2H), 8.11 (1H), 8.54 (1H).

The starting material was prepared as follows:

Example 136a Tert-butyl3-[(5-{N-[2-(cyclopropyloxy)ethyl]carbamoyl}-4-methyl-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

Analogously to Example 1, 189 mg of the title compound was obtained from150 mg of the compound prepared in Example 118c and 140 mg of2-cyclopropoxy-ethylammonium trifluoroacetate (preparable according toExample 154a) and 154b) starting from cyclopropanol and bromoacetamidefollowed by Boc cleavage with trifluoroacetic acid analogously toExample 1a)).

¹H-NMR (300 MHz, DMSO-d6): δ=0.36-0.48 (4H), 1.33 (9H), 2.49 (3H), 3.08(1H), 3.25-3.39 (3H), 3.53 (2H), 3.70 (2H), 3.87 (2H), 4.61 (2H), 7.14(1H), 7.38 (1H), 8.10 (1H), 8.54 (1H).

Example 136b2-(azetidin-3-ylmethyl)-N-[(2-cyclopropyloxy)ethyl]-4-methyl-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 189 mg of the compound prepared inExample 136a, 161 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 137N-[2-(cyclobutyloxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 207 mg of the title compound was obtainedfrom 254 mg of the compound prepared in Example 137b and 166 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.42 (1H), 1.59 (1H), 1.80 (2H), 2.11 (2H),2.50 (3H), 3.17-3.28 (1H), 3.31-3.41 (4H), 3.85-3.95 (2H), 4.10 (1H),4.20 (1H), 4.39 (1H), 4.67 (2H), 7.15 (1H), 7.35-7.44 (3H), 7.71 (2H),8.11 (1H), 8.54 (1H).

The starting material was prepared as follows:

Example 137a Tert-butyl3-[(5-{N-[2-(cyclobutyloxy)ethyl]carbamoyl}-4-methyl-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

Analogously to Example 1, 297 mg of the title compound was obtained from220 mg of the compound prepared in Example 117c and 143 mg of2-(cyclobutyloxy)ethylammonium trifluoroacetate (preparable according toExample 154a) and 154b) starting from cyclobutanol and bromoacetamidefollowed by Boc cleavage with trifluoroacetic acid analogously toExample 1a)).

¹H-NMR (300 MHz, DMSO-d6): δ=1.33 (9H), 1.35-1.49 (1H), 1.59 (1H), 1.80(2H), 2.11 (2H), 2.50 (3H), 3.08 (1H), 3.30-3.41 (4H), 3.69 (2H),3.82-3.95 (3H), 4.61 (2H), 7.15 (1H), 7.38 (1H), 8.10 (1H), 8.54 (1H).

Example 137b2-(azetidin-3-ylmethyl)-N-[(2-(cyclobutyloxy)ethyl]-4-methyl-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 297 mg of the compound prepared inExample 137a, 254 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 138(+/−)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxypropyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 166 mg of the title compound was obtainedfrom 237 mg of the compound prepared in Example 138b and 129 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.07 (3H), 2.49 (3H), 3.14-3.28 (3H), 3.43(1H), 3.89 (1H), 4.08 (1H), 4.19 (1H), 4.36 (1H), 4.67 (2H), 7.15 (1H),7.38 (1H), 7.48 (2H), 7.59 (2H), 8.11 (1H), 8.54 (1H).

The starting material was prepared as follows:

Example 138a (+/−)-tert-butyl3-({5-[N-(2-methoxypropyl)carbamoyl]-4-methyl-2H-indazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1, 331 mg of the title compound was obtained from323 mg of the compound prepared in Example 117c and 117 mg of2-methoxypropylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.08 (3H), 1.33 (9H), 2.50 (3H), 3.09 (1H),3.16-3.31 (2H), 3.44 (1H), 3.69 (2H), 3.85 (2H), 4.61 (2H), 7.15 (1H),7.39 (1H), 8.08 (1H), 8.54 (1H).

Example 138b(+/−)-2-(azetidin-3-ylmethyl)-N-(2-methoxypropyl)-4-methyl-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 280 mg of the compound prepared inExample 138a, 247 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 139 (R orS)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxypropyl)-4-methyl-2H-indazole-5-carboxamide

From 158 mg of the racemate prepared in Example 138, 52 mg of the titlecompound together with 48 mg of the slower-eluting enantiomer (Example140) were obtained by racemate separation by means of preparative chiralHPLC (Method A).

Analytical chiral HPLC: 14.5 min.

Example 140 (S orR)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxypropyl)-4-methyl-2H-indazole-5-carboxamide

From 158 mg of the racemate prepared in Example 138, 48 mg of the titlecompound together with 52 mg of the faster-eluting enantiomer (Example139) were obtained by racemate separation by means of preparative chiralHPLC (Method A).

Analytical chiral HPLC: 17.1 min.

Example 141(+/−)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(1,4-dioxan-2-ylmethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 177 mg of the title compound was obtainedfrom 269 mg of the compound prepared in Example 141b and 136 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.13-3.28 (4H), 3.38-3.66 (4H),3.67-3.77 (2H), 3.89 (1H), 4.08 (1H), 4.19 (1H), 4.37 (1H), 4.67 (2H),7.15 (1H), 7.38 (1H), 7.48 (2H), 7.59 (2H), 8.17 (1H), 8.55 (1H).

The starting material was prepared as follows:

Example 141a (+/−)-tert-butyl3-({5-[N-(1,4-dioxan-2-ylmethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1, 364 mg of the title compound was obtained from323 mg of the compound prepared in Example 117c and 110 mg of1,4-dioxan-2-ylmethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.33 (9H), 2.50 (3H), 3.09 (1H), 3.16-3.29(3H), 3.40-3.77 (8H), 3.86 (2H), 4.61 (2H), 7.16 (1H), 7.39 (1H), 8.14(1H), 8.55 (1H).

Example 141b(+/−)-2-(azetidin-3-ylmethyl)-N-(1,4-dioxan-2-ylmethyl)-4-methyl-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 314 mg of the compound prepared inExample 141a, 274 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 142 (R orS)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(1,4-dioxan-2-yl-methyl)-4-methyl-2H-indazole-5-carboxamide

From 172 mg of the racemate prepared in Example 141, 60 mg of the titlecompound together with 60 mg of the slower-eluting enantiomer (Example143) were obtained by racemate separation by means of preparative chiralHPLC (Method B).

Analytical chiral HPLC: 5.84 min.

Example 143 (S orR)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(1,4-dioxan-2-yl-methyl)-4-methyl-2H-indazole-5-carboxamide

From 172 mg of the racemate prepared in Example 141, 60 mg of the titlecompound together with 60 mg of the faster-eluting enantiomer (Example142) were obtained by racemate separation by means of preparative chiralHPLC (Method B).

Analytical chiral HPLC: 6.28 min.

Example 144(+/−)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 144 mg of the title compound was obtainedfrom 255 mg of the compound prepared in Example 144b and 130 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.10-1.23 (1H), 1.35-1.47 (3H), 1.61 (1H),1.71-1.81 (1H), 2.48 (3H), 3.15-3.27 (4H), 3.37 (1H), 3.80-3.93 (2H),4.08 (1H), 4.19 (1H), 4.36 (1H), 4.66 (2H), 7.14 (1H), 7.37 (1H), 7.48(2H), 7.59 (2H), 8.09 (1H), 8.54 (1H).

The starting material was prepared as follows:

Example 144a (+/−)-tert-butyl3-({4-methyl-5-[N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-carbamoyl]-2H-indazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1, 342 mg of the title compound was obtained from323 mg of the compound prepared in Example 117c and 141 mg of3,4,5,6-tetrahydro-2H-pyran-2-ylmethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.14-1.21 (1H), 1.33 (9H), 1.37-1.49 (3H),1.61 (1H), 1.71-1.80 (1H), 2.49 (3H), 3.09 (1H), 3.21 (2H), 3.27-3.43(2H), 3.69 (2H), 3.81-3.91 (3H), 4.61 (2H), 7.15 (1H), 7.38 (1H), 8.06(1H), 8.53 (1H).

Example 144b(+/−)-2-(azetidin-3-ylmethyl)-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-yl-methyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 298 mg of the compound prepared inExample 144a, 261 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 145 (R orS)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole-5-carboxamide

From 140 mg of the racemate prepared in Example 144, 43 mg of the titlecompound together with 35 mg of the slower-eluting enantiomer (Example146) were obtained by racemate separation by means of preparative chiralHPLC (Method C).

Analytical chiral HPLC: 4.38 min.

Example 146 (S orR)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole-5-carboxamide

From 140 mg of the racemate prepared in Example 144, 35 mg of the titlecompound together with 43 mg of the faster-eluting enantiomer (Example145) were obtained by racemate separation by means of preparative chiralHPLC (Method C).

Analytical chiral HPLC: 4.88 min.

Example 147(+/−)-2-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxypropyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, from 42 mg of the compound prepared in Example138b and 28 mg of 4-(4-fluorophenoxy)benzoic acid, a material stillcontaminated after HPLC purification was obtained, which was furtherpurified by an additional preparative thick layer chromatography withethyl acetate/methanol in the ratio 9:1 as mobile phase. Yield in thismanner: 15 mg of the title compound.

¹H-NMR (300 MHz, CDCl3): δ=1.22 (3H), 2.64 (3H), 3.28 (1H), 3.36 (3H),3.40 (1H), 3.57 (1H), 3.76 (1H), 3.97-4.46 (4H), 4.66 (2H), 6.14 (1H),6.93 (2H), 6.97-7.11 (4H), 7.32 (1H), 7.51 (1H), 7.60 (2H), 8.00 (1H).

Example 148(+/−)-N-(1,4-dioxan-2-ylmethyl)-2-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 18 mg of the title compound was obtained from43 mg of the compound prepared in Example 141b and 26 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.13-3.28 (4H), 3.38-3.66 (4H),3.67-3.77 (2H), 3.89 (1H), 4.07 (1H), 4.19 (1H), 4.37 (1H), 4.66 (2H),6.94 (2H), 7.08-7.18 (3H), 7.24 (2H), 7.38 (1H), 7.60 (2H), 8.17 (1H),8.55 (1H).

Example 1492-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 72 mg of the title compound was obtained from127 mg of the compound prepared in Example 149b and 65 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=0.17 (2H), 0.45 (2H), 0.99 (1H), 2.51-2.54(3H), 3.20-3.28 (3H), 3.38 (2H), 3.51 (2H), 3.92 (1H), 4.11 (1H), 4.21(1H), 4.39 (1H), 4.69 (2H), 7.18 (1H), 7.40 (1H), 7.50 (2H), 7.62 (2H),8.12 (1H), 8.56 (1H).

The starting material was prepared as follows:

Example 149a Tert-butyl3-[(5-{N-[2-(cyclopropylmethoxy)ethyl]carbamoyl}-4-methyl-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

Analogously to Example 1, 448 mg of the title compound was obtained from400 mg of the compound prepared in Example 117c and 133 mg of2-(cyclopropylmethoxy)ethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=0.14 (2H), 0.42 (2H), 0.97 (1H), 1.33 (9H),2.50 (3H), 3.09 (1H), 3.24 (2H), 3.36 (2H), 3.49 (2H), 3.69 (2H), 3.86(2H), 4.61 (2H), 7.15 (1H), 7.38 (1H), 8.08 (1H), 8.54 (1H).

Example 149b2-(azetidin-3-ylmethyl)-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 448 mg of the compound prepared inExample 149a, 390 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 150N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 48 mg of the title compound was obtained from102 mg of the compound prepared in Example 149b and 63 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, CDCl3): δ=0.20 (2H), 0.54 (2H), 1.05 (1H), 2.65 (3H),3.32 (2H), 3.35-3.45 (1H), 3.63-3.75 (4H), 3.99-4.50 (4H), 4.66 (2H),6.22 (1H), 6.93 (2H), 6.97-7.11 (4H), 7.34 (1H), 7.51 (1H), 7.61 (2H),8.00 (1H).

Example 151N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzoyl)azetidin-3-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 55 mg of the title compound was obtained from127 mg of the compound prepared in Example 149b and 46 mg of4-methylbenzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=0.17 (2H), 0.45 (2H), 0.99 (1H), 2.33 (3H),2.53 (3H), 3.19-3.28 (3H), 3.38 (2H), 3.51 (2H), 3.90 (1H), 4.09 (1H),4.20 (1H), 4.38 (1H), 4.69 (2H), 7.18 (1H), 7.24 (2H), 7.41 (1H), 7.50(2H), 8.11 (1H), 8.57 (1H).

Example 1522-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 122 mg of the title compound was obtainedfrom 234 mg of the compound prepared in Example 152b and 115 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.52 (3H), 3.25 (1H), 3.54 (2H), 3.93 (1H),4.11 (1H), 4.17-4.25 (3H), 4.40 (1H), 4.70 (2H), 7.19 (1H), 7.43 (1H),7.50 (2H), 7.61 (2H), 8.38 (1H), 8.58 (1H).

The starting material was prepared as follows:

Example 152a Tert-butyl3-[(4-methyl-5-{N-[2-(trifluoromethoxy)ethyl]carbamoyl}-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

Analogously to Example 1, 272 mg of the title compound was obtained from250 mg of the compound prepared in Example 117c and 120 mg of2-(trifluoromethoxy)ethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ =1.32 (9H), 2.50 (3H), 3.08 (1H), 3.51(2H), 3.70 (2H), 3.86 (2H), 4.17 (2H), 4.61 (2H), 7.16 (1H), 7.41 (1H),8.36 (1H), 8.56 (1H).

Example 152b2-(azetidin-3-ylmethyl)-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 272 mg of the compound prepared inExample 152a, 240 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 153N-(2-tert-butoxyethyl)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55) 12 mg of the title compound was obtained from160 mg of the compound prepared in Example 153b) and 81 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.14 (9H), 2.53 (3H), 3.19-3.34 (3H), 3.43(2H), 3.92 (1H), 4.11 (1H), 4.21 (1H), 4.39 (1H), 4.69 (2H), 7.18 (1H),7.40 (1H), 7.50 (2H), 7.62 (2H), 8.05 (1H), 8.56 (1H).

The starting material was prepared as follows:

Example 153a Tert-butyl3-({5-[N-(2-tert-butoxyethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)azetidin-1-carboxylate

Analogously to Example 1, 284 mg of the title compound was obtained from250 mg of the compound prepared in Example 117c and 111 mg of2-tert-butoxyethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.11 (9H), 1.32 (9H), 2.50 (3H), 3.08 (1H),3.27 (2H), 3.40 (2H), 3.69 (2H), 3.86 (2H), 4.60 (2H), 7.15 (1H), 7.38(1H), 8.04 (1H), 8.54 (1H).

Example 153b2-(azetidin-3-ylmethyl)-N-(2-tert-butoxyethyl)-4-methyl-2H-indazol-5-carboxamidehydrochloride

Analogously to Example 1a, from 284 mg of the compound prepared inExample 153a, 240 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 154(+/−)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(cyclobutyloxy)propyl]-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 135 mg of the title compound was obtainedfrom 222 mg of the compound prepared in Example 154d and 109 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.05 (3H), 1.39 (1H), 1.55 (1H), 1.80 (2H),2.11 (2H), 2.50 (3H), 3.08-3.23 (3H), 3.55 (1H), 3.89 (1H), 4.03-4.13(1H), 4.19 (1H), 4.37 (1H), 4.67 (2H), 7.15 (1H), 7.38 (1H), 7.48 (2H),7.59 (2H), 8.07 (1H), 8.53 (1H).

The starting material was prepared as follows:

Example 154a (+/−)-2-(cyclobutyloxy)-propanamide

To a suspension of 732 mg of sodium hydride in 15 ml THF, 2.0 g ofcyclobutanol in 0.5 ml THF were added dropwise and stirred for 30minutes at 25° C. The reaction mixture was then cooled to 0° C. and 2.11g of (+/−) 2-bromopropanamide in 0.5 ml tetrahydrofuran were addeddropwise and then stirred for 18 hours at 25° C. The reaction mixturewas poured onto ice-water and extracted once with 75 ml dichloromethane.The organic phase was washed with saturated sodium chloride solution,dried over sodium sulphate and concentrated in vacuo after filtration.The crude product thus obtained was purified by column chromatography onsilica gel with hexane/0-50% ethyl acetate. Yield: 0.79 g of the titlecompound.

¹H-NMR (300 MHz, DMSO-d6): δ=1.14 (3H), 1.38 (1H), 1.56 (1H), 1.83 (2H),2.08 (2H), 3.62 (1H), 3.90 (1H), 7.07 (2H).

Example 154b (+/−)-tert-butyl N-[2-(cyclobutyloxy)propyl]carbamate

To a suspension of 6.9 g of lithium aluminium hydride in 250 ml THF, 6.5g of the amide prepared in Example 154a in 81 ml THF were cautiouslyadded dropwise at 0° C. The mixture was then first stirred for 30minutes at 0° C. and then heated for 5 hours under reflux. Aftercooling, the mixture was cautiously treated with 20 g of sodium sulphatedecahydrate and 20 g of potassium fluoride and solid matter removed byfiltration shortly afterwards. The filtrate was concentrated in vacuo.The residue thus obtained (5.8 g) was dissolved without furtherpurification in 174 ml dichloromethane and treated with 11.9 g ofdi-tert-butyl dicarbonate. After 16 hours' stirring at 25° C., this wasconcentrated in vacuo and the residue thus obtained purified by two-foldcolumn chromatography on silica gel with hexane/0-40% ethyl acetate.

Yield: 8.54 g of the title compound.

¹H-NMR (300 MHz, DMSO-d6): δ=0.94 (3H), 1.28-1.42 (10H), 1.53 (1H), 1.76(2H), 2.07 (2H), 2.76 (1H), 2.90 (1H), 3.34 (1H), 3.92 (1H), 6.72 (1H).

Example 154c (+/−)-tert-butyl3-[(5-{N-[2-(cyclobutyloxy)propyl]carbamoyl}-4-methyl-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

Analogously to Example 1a, from 200 mg of the compound prepared inExample 154b), 2-(cyclobutyloxy)propylamine was obtained as thehydrochloride, which without further purification together with 250 mgof the compound prepared in Example 117c analogously to Example 1,yielded 259 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d6): δ=1.05 (3H), 1.32 (9H), 1.39 (1H), 1.55 (1H),1.80 (2H), 2.11 (2H), 2.50 (3H), 3.02-3.17 (2H), 3.22 (1H), 3.54 (1H),3.69 (2H), 3.86 (2H), 3.99 (1H), 4.61 (2H), 7.15 (1H), 7.39 (1H), 8.09(1H), 8.55 (1H).

Example 154d(+/−)-2-(azetidin-3-ylmethyl)-N-[2-(cyclobutyloxy)propyl]-4-methyl-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 259 mg of the compound prepared inExample 154c, 225 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 155 (S orR)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(cyclobutyloxy)-propyl]-4-methyl-2H-indazole-5-carboxamide

From 135 mg of the racemate prepared in Example 154, 41 mg of the titlecompound together with 21 mg of the slower-eluting enantiomer (Example156) were obtained by racemate separation by means of preparative chiralHPLC (Method A).

Analytical chiral HPLC: 10.05 min

Example 156 (R orS)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(cyclobutyloxy)-propyl]-4-methyl-2H-indazole-5-carboxamide

From 135 mg of the racemate prepared in Example 154, 21 mg of the titlecompound together with 41 mg of the faster-eluting enantiomer (Example155) were obtained by racemate separation by means of preparative chiralHPLC (Method A).

Analytical chiral HPLC: 13.14 min

Example 157N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 54 mg of the title compound was obtained from102 mg of the compound prepared in Example 149b and 58 mg of4′-fluorobiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, CDCl3): δ=0.20 (2H), 0.54 (2H), 1.05 (1H), 2.66 (3H),3.32 (2H), 3.42 (1H), 3.61-3.73 (4H), 4.09 (1H), 4.28 (1H), 4.38 (1H),4.49 (1H), 4.69 (2H), 6.22 (1H), 7.10-7.18 (2H), 7.26 (2H), 7.35 (1H),7.50-7.59 (3H), 7.70 (2H), 8.01 (1H).

Example 1582-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 54 mg of the title compound was obtained from108 mg of the compound prepared in Example 117e and 69 mg of4′-fluorobiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.17-3.29 (4H), 3.36 (2H), 3.43(2H), 3.92 (1H), 4.11 (1H), 4.24 (1H), 4.42 (1H), 4.68 (2H), 7.15 (1H),7.29 (2H), 7.39 (1H), 7.63-7.78 (6H), 8.12 (1H), 8.56 (1H).

Example 1592-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 28 mg of the title compound was obtained from108 mg of the compound prepared in Example 117e and 74 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, CDCl3): δ=2.65 (3H), 3.31-3.46 (4H), 3.58 (2H), 3.67(2H), 4.06 (1H), 4.24 (1H), 4.40 (2H), 4.66 (2H), 6.15 (1H), 6.89-7.13(6H), 7.33 (1H), 7.51 (1H), 7.61 (2H), 8.00 (1H).

Example 1602-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 47 mg of the title compound was obtained from115 mg of the compound prepared in Example 129b and 74 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, CDCl3): δ=2.65 (3H), 3.39 (1H), 3.97-4.52 (6H), 4.67(2H), 6.04 (1H), 6.89-7.12 (6H), 7.31 (1H), 7.53 (1H), 7.60 (2H), 8.03(1H).

Example 1612-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 28 mg of the title compound was obtained from115 mg of the compound prepared in Example 129b and 69 mg of4′-fluorobiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.65 (3H), 3.42 (1H), 4.01-4.54 (6H), 4.69(2H), 6.02 (1H), 7.15 (2H), 7.32 (1H), 7.51-7.62 (5H), 7.69 (2H), 8.04(1H).

Example 1622-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoro-ethoxy)ethyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 197 mg of the title compound was obtainedfrom 252 mg of the compound prepared in Example 162a and 108 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.22 (1H), 3.40 (2H), 3.69 (2H),3.90 (1H), 4.03-4.13 (3H), 4.19 (1H), 4.37 (1H), 4.67 (2H), 7.15 (1H),7.38 (1H), 7.48 (2H), 7.59 (2H), 8.19 (1H), 8.55 (1H).

The starting material was prepared as follows:

Example 162a2-(azetidin-3-ylmethyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 583 mg of the compound prepared inExample 162b, 505 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 162b Tert-butyl3-[(4-methyl-5-{N-[2-(2,2,2-trifluoroethoxy)ethyl]carbamoyl}-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

Analogously to Example 1, 580 mg of the title compound was obtained from500 mg of the compound prepared in Example 117c and 260 mg of2-(2,2,2-trifluoroethoxy)ethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.50 (3H), 3.08 (1H), 3.40 (2H),3.61-3.76 (4H), 3.86 (2H), 4.07 (2H), 4.61 (2H), 7.15 (1H), 7.39 (1H),8.18 (1H), 8.55 (1H).

Example 1634-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 89 mg of the title compound was obtained from252 mg of the compound prepared in Example 162a and 175 mg of4-[4-(trifluoromethyl)phenoxy]benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.23 (1H), 3.40 (2H), 3.69 (2H),3.90 (1H), 4.01-4.14 (3H), 4.21 (1H), 4.40 (1H), 4.68 (2H), 7.11 (2H),7.15 (1H), 7.20 (2H), 7.39 (1H), 7.66 (2H), 7.75 (2H), 8.19 (1H), 8.56(1H).

Example 1644-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 64 mg of the title compound was obtained from225 mg of the compound prepared in Example 129b and 149 mg of4-[4-(trifluoromethyl)phenoxy]benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.50 (3H), 3.24 (1H), 3.91 (1H), 3.95-4.15(3H), 4.22 (1H), 4.40 (1H), 4.69 (2H), 7.11 (2H), 7.15-7.23 (3H), 7.43(1H), 7.66 (2H), 7.75 (2H), 8.60 (1H), 8.79 (1H).

Example 1652-({1-[4-(4-chlorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 97 mg of the title compound was obtained from225 mg of the compound prepared in Example 129b and 131 mg of4-(4-chlorophenoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.50 (3H), 3.23 (1H), 3.90 (1H), 3.96-4.12(3H), 4.20 (1H), 4.38 (1H), 4.68 (2H), 7.00 (2H), 7.09 (2H), 7.18 (1H),7.40-7.48 (3H), 7.62 (2H), 8.60 (1H), 8.79 (1H)

Example 1662-({1-[4-(4-chlorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 99 mg of the title compound was obtained from225 mg of the compound prepared in Example 117e and 140 mg of4-(4-chlorophenoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.16-3.27 (4H), 3.36 (2H), 3.42(2H), 3.89 (1H), 4.08 (1H), 4.19 (1H), 4.38 (1H), 4.67 (2H), 7.00 (2H),7.09 (2H), 7.15 (1H), 7.38 (1H), 7.45 (2H), 7.62 (2H), 8.12 (1H), 8.55(1H).

Example 1672-({1-[(5-fluoro-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 48 mg of the title compound was obtained from180 mg of the compound prepared in Example 129b and 82 mg of5-fluoro-1-methyl-1H-indol-2-carboxylic acid.

¹H-NMR (300 MHz, CDCl3): δ=2.66 (3H), 2.80 (3H), 3.36-3.51 (1H), 4.01(3H), 4.04-4.63 (6H), 4.70 (2H), 6.03 (1H), 6.68 (1H), 7.08 (1H),7.22-7.36 (3H), 7.55 (1H), 8.05 (1H).

Example 1682-({1-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 15 mg of the title compound was obtained from180 mg of the compound prepared in Example 129b and 87 mg of5-methoxy-1-methyl-1H-indol-2-carboxylic acid.

¹H-NMR (300 MHz, CDCl3): δ=2.66 (3H), 3.43 (1H), 3.84 (3H), 4.00 (3H),4.03-4.59 (6H), 4.70 (2H), 6.02 (1H), 6.66 (1H), 7.02 (1H), 7.27-7.35(3H), 7.56 (1H), 8.06 (1H).

Example 1692-({1-[(6-methoxy-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 57 mg of the title compound was obtained from180 mg of the compound prepared in Example 129b and 87 mg of6-methoxy-1-methyl-1H-indol-2-carboxylic acid.

¹H-NMR (300 MHz, CDCl3): δ=2.66 (3H), 3.43 (1H), 3.89 (3H), 3.99 (3H),4.05-4.60 (6H), 4.70 (2H), 6.01 (1H), 6.69 (1H), 6.77 (1H), 6.81 (1H),7.32 (1H), 7.48 (1H), 7.56 (1H), 8.05 (1H).

Example 1702-({1-[(5-fluoro-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 95 mg of the title compound was obtained from180 mg of the compound prepared in Example 117e and 87 mg of5-fluoro-1-methyl-1H-indol-2-carboxylic acid.

¹H-NMR (300 MHz, CDCl3): δ=2.65 (3H), 3.35-3.51 (4H), 3.58 (2H), 3.67(2H), 4.01 (3H), 4.02-4.62 (4H), 4.69 (2H), 6.15 (1H), 6.68 (1H), 7.08(1H), 7.21-7.38 (3H), 7.53 (1H), 8.02 (1H).

Example 1712-({1-[(5-chloro-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 90 mg of the title compound was obtained from180 mg of the compound prepared in Example 117e and 95 mg of5-chloro-1-methyl-1H-indol-2-carboxylic acid.

¹H-NMR (300 MHz, CDCl3): δ=2.66 (3H), 3.37-3.49 (4H), 3.58 (2H), 3.67(2H), 4.00 (3H), 4.08 (1H), 4.37 (2H), 4.56 (1H), 4.70 (2H), 6.15 (1H),6.66 (1H), 7.27-7.38 (3H), 7.53 (1H), 7.58 (1H), 8.02 (1H).

Example 172N-(2-methoxyethyl)-2-({1-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 86 mg of the title compound was obtained from180 mg of the compound prepared in Example 117e and 93 mg of5-methoxy-1-methyl-1H-indol-2-carboxylic acid.

¹H-NMR (300 MHz, CDCl3): δ=2.65 (3H), 3.36-3.50 (4H), 3.58 (2H), 3.67(2H), 3.84 (3H), 4.00 (3H), 4.07 (1H), 4.35 (2H), 4.55 (1H), 4.69 (2H),6.15 (1H), 6.66 (1H), 6.97-7.06 (2H), 7.28 (1H), 7.34 (1H), 7.53 (1H),8.02 (1H).

Example 173N-(2-methoxyethyl)-2-({1-[(6-methoxy-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 97 mg of the title compound was obtained from180 mg of the compound prepared in Example 117e and 93 mg of6-methoxy-1-methyl-1H-indol-2-carboxylic acid.

¹H-NMR (300 MHz, CDCl3): δ=2.66 (3H), 3.37-3.47 (4H), 3.58 (2H), 3.67(2H), 3.89 (3H), 3.99 (3H), 4.02-4.60 (4H), 4.69 (2H), 6.15 (1H), 6.69(1H), 6.77 (1H), 6.81 (1H), 7.34 (1H), 7.48 (1H), 7.53 (1H), 8.02 (1H).

Example 174N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)azetidin-3-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 66 mg of the title compound was obtained from135 mg of the compound prepared in Example 117e and 96 mg of4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.50 (3H), 3.18-3.27 (4H), 3.36 (2H), 3.42(2H), 3.91 (1H), 4.10 (1H), 4.24 (1H), 4.42 (1H), 4.68 (2H), 7.15 (1H),7.24 (2H), 7.28 (1H), 7.39 (1H), 7.67 (2H), 8.12 (1H), 8.24 (1H), 8.56(2H).

Example 175N-(2-methoxyethyl)-2-{[1-(7-methoxy-2-naphthoyl)azetidin-3-yl]methyl}-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 72 mg of the title compound was obtained from135 mg of the compound prepared in Example 117e and 69 mg of7-methoxy-naphthalen-2-carboxylic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.50 (3H), 3.21-3.28 (4H), 3.36 (2H), 3.42(2H), 3.85 (3H), 3.93-3.99 (1H), 4.14 (1H), 4.26 (1H), 4.47 (1H), 4.69(2H), 7.15 (1H), 7.22 (1H), 7.38 (1H), 7.43 (1H), 7.50 (1H), 7.81-7.88(2H), 8.05 (1H), 8.12 (1H), 8.56 (1H).

Example 176N-(2-methoxyethyl)-2-{[1-(6-methoxy-2-naphthoyl)azetidin-3-yl]methyl}-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 72 mg of the title compound was obtained from135 mg of the compound prepared in Example 117e and 69 mg of6-methoxynaphthalen-2-carboxylic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.49 (3H), 3.21-3.28 (4H), 3.33-3.39 (2H),3.42 (2H), 3.86 (3H), 3.91-3.98 (1H), 4.13 (1H), 4.27 (1H), 4.48 (1H),4.69 (2H), 7.15 (1H), 7.19 (1H), 7.34 (1H), 7.38 (1H), 7.63 (1H), 7.82(1H), 7.92 (1H), 8.08-8.14 (2H), 8.56 (1H).

Example 1774-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)azetidin-3-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 68 mg of the title compound was obtained from170 mg of the compound prepared in Example 129b and 113 mg of4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.35 (3H), 3.21 (1H), 3.89 (1H), 3.96-4.13(3H), 4.21 (1H), 4.40 (1H), 4.68 (2H), 7.24 (2H), 7.28 (1H), 7.40 (1H),7.66 (2H), 7.72 (1H), 8.24 (1H), 8.48 (1H), 8.56 (1H), 8.89 (1H).

Example 1782-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 154 mg of the title compound was obtainedfrom 210 mg of the compound prepared in Example 178e and 119 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.19 (1H), 3.24 (3H), 3.34 (2H),3.42 (2H), 3.87 (1H), 4.07 (1H), 4.16 (1H), 4.34 (1H), 4.65 (2H), 7.35(1H), 7.48 (2H), 7.59 (2H), 7.63 (1H), 8.21 (1H), 8.41 (1H).

The starting material was prepared as follows:

Example 178a Tert-butyl3-[(5-bromo-6-methyl-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

To a solution of 6.18 g of 5-bromo-6-methyl-1H-indazole and 15 g oftert-butyl-3-[(tosyl-oxy)methyl]azetidin-1-carboxylate in 200 ml DMFwere added 9.54 g of caesium carbonate and 10.8 g of tetrabutylammoniumiodide at 25° C., and this was then heated under reflux for 1.5 hrs.After cooling, the reaction mixture was treated with 1:1 hexane/etherand water, the phases separated and the aqueous phase extracted twicewith 250 ml portions of 1:1 hexane/ether. The combined organic phaseswere washed with saturated sodium chloride solution, dried over sodiumsulphate, and concentrated in vacuo after filtration.

The residue thus obtained was purified by twofold column chromatographyon silica gel with hexane/0-20% ethyl acetate. 2.88 g of the titlecompound was obtained.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.37 (3H), 3.05 (1H), 3.67 (2H),3.85 (2H), 4.59 (2H), 7.56 (1H), 7.97 (1H), 8.33 (1H).

Example 178b Methyl2-{[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}-6-methyl-2H-indazol-5-carboxylate

To a solution of 730 mg of the bromide prepared in Example 178a in 17.5ml tetrahydrofuran were added 0.23 ml of methanol, 145 mg oftrans-bis(acetato)-bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II),877 mg of DBU and 760 mg of molybdenum hexacarbonyl This reactionmixture was then heated in the microwave (120 watts) for 20 minutes at125° C. Seven further preparations were performed in the same manner andall worked up together. For this, they were concentrated in vacuo andthe residue taken up in water and ethyl acetate. After phase separation,the aqueous phase was extracted three times with 75 ml portions of ethylacetate and the combined organic phases washed with saturated sodiumchloride solution, dried over sodium sulphate and concentrated in vacuoafter filtration. The residue thus obtained was purified by twofoldcolumn chromatography on silica gel with hexane/0-30% ethyl acetate.Yield: 4.0 g of the title compound.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.52 (3H), 3.07 (1H), 3.69 (2H),3.86 (2H), 3.78 (3H), 4.62 (2H), 7.43 (1H), 8.33 (1H), 8.53 (1H).

Example 178c2-{[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}-6-methyl-2H-indazol-5-carboxylicacid

Analogously to Example 1d, 3.2 g of the title compound was obtained from4.0 g of the ester prepared in Example 178b.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.53 (3H), 3.07 (1H), 3.69 (2H),3.86 (2H), 4.61 (2H), 7.39 (1H), 8.31 (1H), 8.50 (1H), 12.48 (1H).

Example 178d Tert-butyl3-({5-[1\1-(2-methoxyethyl)carbamoyl]-6-methyl-2H-indazol-2-yl}-methyl)azetidin-1-carboxylate

Analogously to Example 1, 603 mg of the title compound was obtained from500 mg of the acid prepared in Example 178c and 109 mg of2-methoxyethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.34 (3H), 3.06 (1H), 3.25 (3H),3.32-3.45 (4H), 3.67 (2H), 3.84 (2H), 4.59 (2H), 7.35 (1H), 7.64 (1H),8.21 (1H), 8.41 (1H).

Example 178e2-(azetidin-3-ylmethyl)-N-(2-methoxyethyl)-6-methyl-2H-indazol-5-carboxamidehydrochloride

Analogously to Example 1a, from 250 mg of the amide prepared in Example178d, 275 mg of the title compound was obtained, which was reactedwithout further purification.

Example 1792-{[1-(3,5-Difluorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 51 mg of the title compound was obtained from77 mg of the compound prepared in Example 178e and 44 mg of3,5-difluorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.33 (3H), 3.18 (1H), 3.24 (3H), 3.34 (2H),3.42 (2H), 3.87 (1H), 4.03-4.11 (1H), 4.20 (1H), 4.38 (1H), 4.65 (2H),7.20-7.28 (2H), 7.34 (1H), 7.36-7.45 (2H), 7.64 (1H), 8.22 (1H), 8.42(1H).

Example 180N-(2-methoxyethyl)-6-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 30 mg of the title compound was obtained from43 mg of the compound prepared in Example 178e and 34 mg of4-[(trifluoromethyl)sulphanyl]benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.20 (1H), 3.24 (3H), 3.34 (2H),3.42 (2H), 3.89 (1H), 4.09 (1H), 4.17 (1H), 4.36 (1H), 4.65 (2H), 7.34(1H), 7.63 (1H), 7.69 (2H), 7.76 (2H), 8.21 (1H), 8.41 (1H).

Example 181N-(2-methoxyethyl)-6-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 221 mg of the title compound was obtainedfrom 294 mg of the compound prepared in Example 178e and 214 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.20 (1H), 3.25 (3H), 3.34 (2H),3.42 (2H), 3.89 (1H), 4.08 (1H), 4.18 (1H), 4.36 (1H), 4.65 (2H), 7.35(1H), 7.40 (2H), 7.64 (1H), 7.70 (2H), 8.21 (1H), 8.42 (1H).

Example 1822-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxy-ethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 11 mg of the title compound was obtained from43 mg of the compound prepared in Example 178e and 32 mg of2-fluoro-4-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.33 (3H), 3.20 (1H), 3.24 (3H), 3.35 (2H),3.42 (2H), 3.86-3.95 (2H), 4.02-4.16 (2H), 4.65 (2H), 7.34 (1H),7.61-7.69 (3H), 7.79 (1H), 8.21 (1H), 8.41 (1H).

Example 1832-{[1-(4-chloro-2-fluorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, from 70 mg of the compound prepared inExample 178e and 44 mg of 4-chloro-2-fluorobenzoyl chloride, a materialstill contaminated after HPLC purification was obtained, which wasfurther purified by additional preparative thick layer chromatographywith ethyl acetate/methanol in the ratio 9:1 as mobile phase. Thisyielded 12 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.19 (1H), 3.25 (3H), 3.34 (2H),3.42 (2H), 3.84-3.93 (2H), 4.02-4.10 (2H), 4.64 (2H), 7.32-7.36 (2H),7.46 (1H), 7.53 (1H), 7.63 (1H), 8.22 (1H), 8.41 (1H).

Example 1842-({1-[3-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxy-ethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 32 mg of the title compound was obtained from70 mg of the compound prepared in Example 178e and 52 mg of3-fluoro-4-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.20 (1H), 3.24 (3H), 3.30-3.38(2H), 3.42 (2H), 3.90 (1H), 4.10 (1H), 4.19 (1H), 4.38 (1H), 4.66 (2H),7.34 (1H), 7.57 (1H), 7.60-7.67 (2H), 7.85 (1H), 8.21 (1H), 8.41 (1H).

Example 1852-({1-[4-chloro-3-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxy-ethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 30 mg of the title compound was obtained from70 mg of the compound prepared in Example 178e and 55 mg of4-chloro-3-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.19 (1H), 3.24 (3H), 3.34 (2H),3.42 (2H), 3.89 (1H), 4.10 (1H), 4.20 (1H), 4.35-4.43 (1H), 4.65 (2H),7.33 (1H), 7.64 (1H), 7.78 (1H), 7.85 (1H), 7.93 (1H), 8.21 (1H), 8.40(1H).

Example 186N-(2-methoxyethyl)-6-methyl-2-({1-[4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 31 mg of the title compound was obtained from70 mg of the compound prepared in Example 178e and 47 mg of4-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.20 (1H), 3.24 (3H), 3.35 (2H),3.42 (2H), 3.90 (1H), 4.06-4.21 (2H), 4.35 (1H), 4.66 (2H), 7.34 (1H),7.63 (1H), 7.73-7.82 (4H), 8.21 (1H), 8.41 (1H).

Example 1876-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]azetidin-3-yl}methyl)-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 35 mg of the title compound was obtained from170 mg of the compound prepared in Example 187b and 103 mg of4-(pentafluoro-29-sulphanyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.36 (3H), 3.12-3.23 (3H), 3.49 (2H), 3.91(1H), 4.06-4.21 (2H), 4.36 (1H), 4.66 (2H), 7.36 (1H), 7.69 (1H), 7.76(2H), 7.95 (2H), 8.44 (1H), 8.46 (1H).

The starting material was prepared as follows:

Example 187a Tert-butyl3-{[6-methyl-5-(N-{2-[(trifluoromethyl)sulphanyl]ethyl}carbamoyl)-2H-indazol-2-yl]methyl}azetidin-1-carboxylate

Analogously to Example 1, 998 mg of the title compound was obtained from800 mg of the acid prepared in Example 178c and 336 mg of2-[(trifluoromethyl)sulphanyl]ethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.36 (3H), 3.06 (1H), 3.13-3.21(2H), 3.49 (2H), 3.67 (2H), 3.84 (2H), 4.59 (2H), 7.37 (1H), 7.70 (1H),8.44 (1H), 8.47 (1H).

Example 187b2-(azetidin-3-ylmethyl)-6-methyl-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a), from 395 mg of the amide prepared in Example187a), 402 mg of the title compound was obtained, which was reactedwithout further purification.

Example 1886-methyl-2-({-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]azetidin-3-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 25 mg of the title compound was obtained from136 mg of the compound prepared in Example 188b and 93 mg of4-(pentafluoro-λ⁶-sulphanyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.20 (1H), 3.91 (1H), 3.95-4.21(4H), 4.36 (1H), 4.67 (2H), 7.38 (1H), 7.71 (1H), 7.76 (2H), 7.95 (2H),8.45 (1H), 8.86 (1H).

The starting material was prepared as follows:

Example 188a Tert-butyl3-({6-methyl-5-[N-(2,2,2-trifluoroethyl)carbamoyl]-2H-indazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1, 550 mg of the title compound was obtained from560 mg of the acid prepared in Example 178c and 160 mg of2,2,2-trifluoroethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.34 (3H), 3.06 (1H), 3.67 (2H),3.84 (2H), 3.93-4.10 (2H), 4.60 (2H), 7.40 (1H), 7.71 (1H), 8.46 (1H),8.88 (1H).

Example 188b2-(azetidin-3-ylmethyl)-6-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 550 mg of the amide prepared in Example188a, 530 mg of the title compound was obtained, which was reactedwithout further purification.

Example 1892-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-6-methyl-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 45 mg of the title compound was obtained from170 mg of the compound prepared in Example 187b and 80 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.39 (3H), 3.17-3.27 (3H), 3.52 (2H), 3.90(1H), 4.10 (1H), 4.19 (1H), 4.37 (1H), 4.68 (2H), 7.39 (1H), 7.50 (2H),7.61 (2H), 7.72 (1H), 8.47 (1H), 8.49 (1H).

Example 1902-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-6-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 60 mg of the title compound was obtained from136 mg of the compound prepared in Example 188b and 72 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.20 (1H), 3.87 (1H), 3.94-4.11(3H), 4.16 (1H), 4.35 (1H), 4.66 (2H), 7.39 (1H), 7.48 (2H), 7.59 (2H),7.71 (1H), 8.46 (1H), 8.89 (1H).

Example 191(+/−)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-6-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 49 mg of the title compound was obtained from120 mg of the compound prepared in Example 191b and 61 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.08-1.23 (1H), 1.36-1.49 (3H), 1.62 (1H),1.72-1.80 (1H), 2.34 (3H), 3.10-3.43 (5H), 3.80-3.92 (2H), 4.07 (1H),4.16 (1H), 4.34 (1H), 4.65 (2H), 7.34 (1H), 7.47 (2H), 7.59 (2H), 7.63(1H), 8.16 (1H), 8.40 (1H).

The starting material was prepared as follows:

Example 191a (+/−)-tert-butyl3-({6-methyl-5-[N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-carbamoyl]-2H-indazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1, 140 mg of the title compound was obtained from300 mg of the acid prepared in Example 178c and 105 mg of3,4,5,6-tetrahydro-2H-pyran-2-ylmethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.07-1.24 (1H), 1.27-1.49 (12H), 1.62 (1H),1.76 (1H), 2.33 (3H), 3.06 (1H), 3.20 (2H), 3.29-3.45 (2H), 3.67 (2H),3.78-3.90 (3H), 4.59 (2H), 7.35 (1H), 7.63 (1H), 8.16 (1H), 8.40 (1H).

Example 191b(+/−)-2-(azetidin-3-ylmethyl)-6-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 140 mg of the amide prepared in Example191a, 132 mg of the title compound was obtained, which was reactedwithout further purification.

Example 192(+/−)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxypropyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 89 mg of the title compound was obtained from151 mg of the compound prepared in Example 192b and 82 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.08 (3H), 2.34 (3H), 3.13-3.32 (6H), 3.43(1H), 3.87 (1H), 4.07 (1H), 4.16 (1H), 4.34 (1H), 4.65 (2H), 7.35 (1H),7.48 (2H), 7.59 (2H), 7.63 (1H), 8.18 (1H), 8.41 (1H).

The starting material was prepared as follows:

Example 192a (+/−)-tert-butyl3-({5-[N-(2-methoxypropyl)carbamoyl]-6-methyl-2H-indazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1, 358 mg of the title compound was obtained from300 mg of the acid prepared in Example 178c and 77 mg of2-methoxypropan-1-amine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.08 (3H), 1.32 (9H), 2.34 (3H), 3.06 (1H),3.13-3.31 (5H), 3.43 (1H), 3.67 (2H), 3.84 (2H), 4.59 (2H), 7.35 (1H),7.64 (1H), 8.18 (1H), 8.40 (1H).

Example 192b(+/−)-2-(azetidin-3-ylmethyl)-N-(2-methoxypropyl)-6-methyl-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a), from 358 mg of the amide prepared in Example192a), 319 mg of the title compound was obtained, which was reactedwithout further purification.

Example 193(+/−)-N-(2-methoxypropyl)-6-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]-azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 87 mg of the title compound was obtained from151 mg of the compound prepared in Example 192b and 106 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.08 (3H), 2.34 (3H), 3.13-3.31 (6H), 3.43(1H), 3.88 (1H), 4.08 (1H), 4.17 (1H), 4.36 (1H), 4.65 (2H), 7.35 (1H),7.40 (2H), 7.64 (1H), 7.70 (2H), 8.18 (1H), 8.41 (1H).

Example 1946-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 87 mg of the title compound was obtained from173 mg of the compound prepared in Example 187b and 105 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.36 (3H), 3.11-3.24 (3H), 3.49 (2H), 3.89(1H), 4.09 (1H), 4.17 (1H), 4.36 (1H), 4.66 (2H), 7.36 (1H), 7.40 (2H),7.66-7.74 (3H), 8.44 (1H), 8.46 (1H).

Example 1956-methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 70 mg of the title compound was obtained from170 mg of the compound prepared in Example 188b and 116 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.35 (3H), 3.21 (1H), 3.89 (1H), 3.95-4.13(3H), 4.18 (1H), 4.36 (1H), 4.67 (2H), 7.40 (3H), 7.66-7.75 (3H), 8.45(1H), 8.86 (1H).

Example 1966-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 22 mg of the title compound was obtained from179 mg of the compound prepared in Example 196b and 113 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.20 (1H), 3.50 (2H), 3.89 (1H),4.08 (1H), 4.14-4.21 (3H), 4.36 (1H), 4.66 (2H), 7.36 (1H), 7.40 (2H),7.66 (1H), 7.70 (2H), 8.44 (1H), 8.46 (1H).

The starting material was prepared as follows:

Example 196a Tert-butyl3-[(6-methyl-5-{N-[2-(trifluoromethoxy)ethyl]carbamoyl}-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

Analogously to Example 1, 417 mg of the title compound was obtained from300 mg of the acid prepared in Example 178c and 144 mg of2-(trifluoromethoxy)ethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 2.34 (3H), 3.06 (1H), 3.50 (2H),3.68 (2H), 3.84 (2H), 4.16 (2H), 4.59 (2H), 7.37 (1H), 7.66 (1H), 8.44(1H), 8.46 (1H).

Example 196b2-(azetidin-3-ylmethyl)-6-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 417 mg of the amide prepared in Example196a, 369 mg of the title compound was obtained, which was reactedwithout further purification.

Example 1972-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-6-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 41 mg of the title compound was obtained from179 mg of the compound prepared in Example 196b and 88 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.19 (1H), 3.50 (2H), 3.87 (1H),4.07 (1H), 4.13-4.21 (3H), 4.34 (1H), 4.65 (2H), 7.36 (1H), 7.48 (2H),7.59 (2H), 7.66 (1H), 8.44 (1H), 8.46 (1H).

Example 1982-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 107 mg of the title compound was obtainedfrom 214 mg of the compound prepared in Example 198b and 109 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=0.14 (2H), 0.42 (2H), 0.97 (1H), 2.34 (3H),3.12-3.26 (3H), 3.34 (2H), 3.47 (2H), 3.87 (1H), 4.07 (1H), 4.16 (1H),4.34 (1H), 4.65 (2H), 7.35 (1H), 7.48 (2H), 7.59 (2H), 7.63 (1H), 8.21(1H), 8.42 (1H).

The starting material was prepared as follows:

Example 198a Tert-butyl3-[(5-{N-[2-(cyclopropylmethoxy)ethyl]carbamoyl}-6-methyl-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

Analogously to Example 1, 247 mg of the title compound was obtained from245 mg of the acid prepared in Example 178c and 82 mg of2-(cyclopropylmethoxy)ethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=0.14 (2H), 0.43 (2H), 0.97 (1H), 1.32 (9H),2.35 (3H), 3.06 (1H), 3.23 (2H), 3.34 (2H), 3.48 (2H), 3.67 (2H), 3.85(2H), 4.59 (2H), 7.35 (1H), 7.64 (1H), 8.18 (1H), 8.41 (1H).

Example 198b2-(azetidin-3-ylmethyl)-N-[2-(cyclopropylmethoxy)ethyl]-6-methyl-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 247 mg of the amide prepared in Example198a, 214 mg of the title compound was obtained, which was reactedwithout further purification.

Example 1992-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-6-methyl-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 56 mg of the title compound was obtained from173 mg of the compound prepared in Example 187b and 98 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.38 (3H), 3.16-3.27 (3H), 3.52 (2H), 3.90(1H), 4.08 (1H), 4.19 (1H), 4.38 (1H), 4.68 (2H), 6.97 (2H), 7.14 (2H),7.27 (2H), 7.39 (1H), 7.62 (2H), 7.72 (1H), 8.47 (1H), 8.49 (1H).

Example 2002-{[1-(4-cyclopropylbenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 86 mg of the title compound was obtained from168 mg of the compound prepared in Example 178e and 80 mg of4-cyclopropylbenzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=0.71 (2H), 0.99 (2H), 1.95 (1H), 2.37 (3H),3.21 (1H), 3.27 (3H), 3.37 (2H), 3.45 (2H), 3.88 (1H), 4.07 (1H), 4.17(1H), 4.35 (1H), 4.67 (2H), 7.12 (2H), 7.38 (1H), 7.47 (2H), 7.66 (1H),8.22 (1H), 8.44 (1H).

Example 2016-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 71 mg of the title compound was obtained from180 mg of the compound prepared in Example 188b and 95 mg of4-[4-(trifluoromethyl)phenoxy]benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.21 (1H), 3.88 (1H), 3.95-4.13(3H), 4.19 (1H), 4.37 (1H), 4.67 (2H), 7.11 (2H), 7.19 (2H), 7.39 (1H),7.65 (2H), 7.69-7.79 (3H), 8.47 (1H), 8.88 (1H).

Example 202N-(2-methoxyethyl)-6-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 108 mg of the title compound was obtained from180 mg of the compound prepared in Example 178e and 102 mg of4-[4-(trifluoromethyl)phenoxy]benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.14-3.26 (4H), 3.34 (2H), 3.42(2H), 3.88 (1H), 4.07 (1H), 4.19 (1H), 4.37 (1H), 4.66 (2H), 7.11 (2H),7.19 (2H), 7.35 (1H), 7.61-7.68 (3H), 7.75 (2H), 8.21 (1H), 8.42 (1H).

Example 2032-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-6-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 104 mg of the title compound was obtained from180 mg of the compound prepared in Example 188b and 73 mg of4′-fluorobiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.22 (1H), 3.90 (1H), 3.95-4.14(3H), 4.21 (1H), 4.40 (1H), 4.68 (2H), 7.28 (2H), 7.40 (1H), 7.60-7.77(7H), 8.48 (1H), 8.89 (1H).

Example 2042-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxy-ethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 73 mg of the title compound was obtained from180 mg of the compound prepared in Example 178e and 78 mg of4′-fluorobiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=2.34 (3H), 3.14-3.26 (4H), 3.34 (2H), 3.41(2H), 3.89 (1H), 4.09 (1H), 4.21 (1H), 4.39 (1H), 4.66 (2H), 7.28 (2H),7.35 (1H), 7.61-7.77 (7H), 8.21 (1H), 8.43 (1H).

Example 2052-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, from 85 mg of the compound prepared inExample 205c and 45 mg of 4-chlorobenzoyl chloride, a material stillcontaminated after column chromatography was obtained which was furtherpurified by additional preparative thick layer chromatography withdichloromethane/methanol in the ratio 95:5 as mobile phase. Yield: 48 mgof the title compound.

¹H-NMR (300 MHz, DMSO-d6): δ=1.09-1.53 (4H), 2.24 (1H), 2.34 (3H), 2.71(1H), 2.97 (1H), 3.24 (3H), 3.34 (2H), 3.38-3.54 (3H), 7.31-7.37 (3H),7.46 (2H), 7.63 (1H), 8.21 (1H), 8.33 (H).

The starting material was prepared as follows:

Example 205a Tert-butyl4-[(5-bromo-6-methyl-2H-indazol-2-yl)methyl]piperidin-1-carboxylate

Analogously to Example 1c, 2.99 g of the title compound was obtainedfrom 5.7 g of 5-bromo-6-methyl-1H-indazole and 15.0 g oftert-butyl-4-[(tosyloxy)methyl]piperidin-1-carboxylate.

¹H-NMR (300 MHz, CDCl3): δ=1.14-1.30 (2H), 1.44 (9H), 1.53 (2H), 2.24(1H), 2.50 (3H), 2.66 (2H), 4.11 (2H), 4.23 (2H), 7.55 (1H), 7.77 (1H),7.87 (1H).

Example 205b Tert-butyl4-({5-[N-(2-methoxyethyl)carbamoyl]-6-methyl-2H-indazol-2-yl}-methyl)piperidin-1-carboxylate

Analogously to Example 1b, 3.56 g of the title compound was obtainedfrom 600 mg of the bromide prepared in Example 205a and 331 mg of2-methoxyethylamine after four runs and twofold purification bychromatography.

¹H-NMR (300 MHz, DMSO-d6): δ=0.96-1.15 (2H), 1.29-1.42 (10H), 2.03-2.18(1H), 2.34 (3H), 2.51-2.73 (3H), 3.25 (3H), 3.31-3.45 (4H), 3.86 (2H),4.26 (2H), 7.35 (1H), 7.63 (1H), 8.21 (1H), 8.32 (1H).

Example 205cN-(2-methoxyethyl)-6-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 100 mg of the amide prepared in Example205b, 85 mg of the title compound was obtained, which was reactedwithout further purification.

Example 2062-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, from 85 mg of the compound prepared inExample 205c and 58 mg of 2-fluoro-4-(trifluoromethyl)benzoyl chloride,a material still contaminated after column chromatography was obtainedwhich was further purified by additional preparative thick layerchromatography with dichloromethane/methanol in the ratio 95:5 as mobilephase. Yield: 40 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d6): δ=1.03-1.28 (2H), 1.37 (1H), 1.53 (1H), 2.23(1H), 2.34 (3H), 2.77 (1H), 3.00 (1H), 3.26-3.49 (11H), 4.30 (2H), 4.44(1H), 7.35 (1H), 7.54-7.67 (3H), 7.78 (1H), 8.21 (1H), 8.34 (1H).

Example 2072-{[1-(4-chloro-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 68 mg of the title compound was obtained from85 mg of the compound prepared in Example 205c and 49 mg of4-chloro-2-fluorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.04-1.25 (2H), 1.37 (1H), 1.51 (1H), 2.23(1H), 2.34 (3H), 2.73 (1H), 2.98 (1H), 3.21-3.48 (3H), 3.30-3.38 (3H),3.42 (2H), 4.29 (2H), 4.42 (1H), 7.29-7.42 (3H), 7.51 (1H), 7.63 (1H),8.21 (1H), 8.33 (1H).

Example 2082-({1-[3-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 70 mg of the title compound was obtained from85 mg of the compound prepared in Example 205c and 58 mg of3-fluoro-4-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.13-1.27 (2H), 1.35 (1H), 1.51 (1H), 2.23(1H), 2.34 (3H), 2.74 (1H), 2.98 (1H), 3.22-3.45 (8H), 4.29 (2H), 4.40(1H), 7.32-7.38 (2H), 7.52 (1H), 7.63 (1H), 7.82 (1H), 8.21 (1H), 8.33(1H).

Example 2092-({1-[4-chloro-3-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 92 mg of the title compound was obtained from85 mg of the compound prepared in Example 205c and 62 mg of4-chloro-3-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.14-1.28 (2H), 1.35 (1H), 1.44-1.53 (1H),2.25 (1H), 2.34 (3H), 2.74 (1H), 3.01 (1H), 3.24 (3H), 3.34 (2H),3.39-3.50 (3H), 4.29 (2H), 4.39 (1H), 7.35 (1H), 7.61-7.68 (2H),7.74-7.80 (2H), 8.21 (1H), 8.33 (1H).

Example 210N-(2-methoxyethyl)-6-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 126 mg of the title compound was obtained from85 mg of the compound prepared in Example 205c and 58 mg of4-(pentafluoro-λ⁶-sulphanyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=1.12-1.27 (2H), 1.35 (1H), 1.51 (1H), 2.24(1H), 2.34 (3H), 2.74 (1H), 2.99 (1H), 3.24 (3H), 3.34-3.46 (5H), 4.30(2H), 4.41 (1H), 7.35 (1H), 7.55 (2H), 7.63 (1H), 7.94 (2H), 8.21 (1H),8.33 (1H).

Example 211N-(2-methoxyethyl)-6-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 69 mg of the title compound was obtained from85 mg of the compound prepared in Example 205c and 53 mg of4-(trifluoromethyl)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.10-1.26 (2H), 1.35 (1H), 1.51 (1H),2.19-2.30 (1H), 2.34 (3H), 2.74 (1H), 2.98 (1H), 3.21-3.47 (8H), 4.30(2H), 4.42 (1H), 7.35 (1H), 7.54 (2H), 7.63 (1H), 7.77 (2H), 8.21 (1H),8.33 (1H).

Example 2122-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-ethyl-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 61 mg of the title compound was obtained from91 mg of the compound prepared in Example 212i and 46 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.14-1.28 (5H), 1.31-1.60 (2H), 2.27 (1H),2.63-3.04 (4H), 3.24 (3H), 3.31-3.56 (5H), 4.31 (2H), 4.39 (1H), 7.10(1H), 7.32-7.41 (3H), 7.46 (2H), 8.11 (1H), 8.50 (1H).

The starting material was prepared as follows:

Example 212a 4-bromo-3-ethyl-2-methylaniline

A suspension of 3 g of 3-ethyl-2-methylaniline hydrochloride in 200 mlethyl acetate was washed twice with 30 ml portions of saturated sodiumcarbonate solution and twice with 20 ml portions of saturated sodiumchloride solution, dried over sodium sulphate and concentrated in vacuoafter filtration. This yielded 2.69 g of ethyl-2-methylaniline, whichwas further reacted without purification.

To a solution of 2.36 g of the amine prepared above in 29 ml DMF, asolution of 3.1 g of N-bromosuccinimide in 14.5 ml DMF was addeddropwise at 0° C. and stirred for 30 minutes at 0° C. Then the reactionmixture was diluted with 400 ml ethyl acetate and washed once with 30 mlof a 10% aqueous sodium carbonate solution and once with 30 ml water.After drying over sodium sulphate and filtration, this was concentratedin vacuo. The crude product thus obtained (3.86 g) was used in the nextstep without purification.

Example 212b N-(4-bromo-3-ethyl-2-methylphenyl)acetamide

To a solution of 3.86 g of the bromide prepared in Example 212a in 48 mlpyridine, 2.04 ml of acetic anhydride was added dropwise at 0° C. andstirred for 20 hours at 25° C. The reaction mixture was concentrated invacuo and the crude product thus obtained was purified by columnchromatography on silica gel with hexane/0-100% ethyl acetate. In thismanner, 3.73 g of the title compound was obtained.

¹H-NMR (300 MHz, CDCl3): δ=1.13 (3H), 2.20 (3H), 2.25 (3H), 2.86 (2H),6.91 (1H), 7.33 (1H), 7.40 (1H).

Example 212c 1-(5-bromo-4-ethyl-1H-indazol-1-yl)ethan-1-one

To a solution of 3.72 g of the acetamide prepared in Example 212b in31.5 ml chloroform were added 4.1 ml of acetic anhydride and 2.85 g ofpotassium acetate, and 192 mg of 18-crown-6 and 3.4 g of isopentylnitrite were then added dropwise. The reaction mixture was heated for 20hours under reflux and after cooling diluted with 200 ml ethyl acetate.The organic phase was washed with 20 ml sodium carbonate solution andonce with saturated sodium chloride solution. After drying over sodiumsulphate and filtration, this was concentrated in vacuo and the crudeproduct thus obtained purified by column chromatography on silica gelwith hexane/0-50% ethyl acetate. Yield: 3.78 g of the title compound.

¹H-NMR (300 MHz, DMSO-d6): δ=1.18 (3H), 2.68 (3H), 3.04 (2H), 7.73 (1H),8.03 (1H), 8.64 (1H).

Example 212d 5-bromo-4-ethyl-1H-indazole

A mixture of 3.78 g of the compound prepared in Example 212c in 7.3 mlmethanol and 26.3 ml of 37% hydrochloric acid was heated under refluxfor 2 hours. This was then diluted with 400 ml ethyl acetate. Theorganic phase was washed three times with 50 ml portions of sodiumhydrogen carbonate solution and once with 50 ml saturated sodiumchloride solution, dried over sodium sulphate and concentrated in vacuo.The crude product thus obtained was purified by column chromatography onsilica gel with hexane/0-50% ethyl acetate. Yield: 2.97 g of the titlecompound.

¹H-NMR (300 MHz, DMSO-d6): δ=1.17 (3H), 2.98 (2H), 7.30 (1H), 7.41 (1H),8.16 (1H), 13.17 (1H).

Example 212e Tert-butyl4-[(5-bromo-4-ethyl-2H-indazol-2-yl)methyl]piperidin-1-carboxylate

Analogously to Example 1c, 961 mg of the title compound was obtainedfrom 2.97 g of the indazole prepared in Example 212d and 7.3 g oftert-butyl-4-[(tosyloxy)methyl]piperidin-1-carboxylate.

¹H-NMR (300 MHz, DMSO-d6): δ=1.01-1.13 (2H), 1.16 (3H), 1.34 (9H), 1.41(2H), 2.12 (1H), 2.63 (2H), 2.90 (2H), 3.87 (2H), 4.27 (2H), 7.27 (1H),7.35 (1H), 8.49 (1H).

Example 212f Methyl2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-4-ethyl-2H-indazol-5-carboxylate

Analogously to Example 1e, after two runs 571 mg of the title compoundwas obtained from 347 mg of the bromide prepared in Example 212e and 0.1ml of methanol.

¹H-NMR (300 MHz, DMSO-d6): δ=1.02-1.15 (2H), 1.17-1.24 (3H), 1.34 (9H),1.42 (2H), 2.14 (1H), 2.63 (2H), 3.17 (2H), 3.79 (3H), 3.88 (2H), 4.30(2H), 7.43 (1H), 7.60 (1H), 8.68 (1H).

Example 212g2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-4-ethyl-2H-indazol-5-carboxylicacid

Analogously to Example 1d, 427 mg of the title compound was obtainedfrom 371 mg of the ester in Example 212f.

¹H-NMR (300 MHz, DMSO-d6): δ=1.00-1.15 (2H), 1.20 (3H), 1.34 (9H), 1.42(2H), 2.14 (1H), 2.64 (2H), 3.19 (2H), 3.88 (2H), 4.29 (2H), 7.39 (1H),7.61 (1H), 8.63 (1H), 12.33 (1H).

Example 212h Tert-butyl4-({4-ethyl-5-[N-(2-methoxyethyl)carbamoyl]-2H-indazol-2-yl}-methyl)piperidin-1-carboxylate

Analogously to Example 1, 215 mg of the title compound was obtained from427 mg of the acid prepared in Example 212g and 83 mg of2-methoxy-ethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=0.98-1.14 (2H), 1.19 (3H), 1.30-1.47 (11H),2.13 (1H), 2.65 (2H), 2.90 (2H), 3.24 (3H), 3.32-3.45 (4H), 3.87 (2H),4.28 (2H), 7.10 (1H), 7.38 (1H), 8.12 (1H), 8.50 (1H).

Example 212i4-ethyl-N-(2-methoxyethyl)-2-(4-piperidylmethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 215 mg of the amide prepared in Example212h, 258 mg of the title compound was obtained, which was reactedwithout further purification.

Example 2134-Ethyl-N-(2-methoxyethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 32 mg of the title compound was obtained from91 mg of the compound prepared in Example 212i and 59 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.14-1.29 (5H), 1.31-1.61 (2H), 2.20-2.35(1H), 2.66-3.06 (4H), 3.24 (3H), 3.30-3.56 (5H), 4.31 (2H), 4.41 (1H),7.10 (1H), 7.34-7.43 (3H), 7.47 (2H), 8.11 (1H), 8.50 (1H).

Example 2142-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 691 mg of the title compound was obtainedfrom 68 mg of the compound prepared in Example 214c and 37 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=3.22 (1H), 3.27 (3H), 3.40-3.47 (4H), 3.92(1H), 4.10 (1H), 4.16 (3H), 4.19 (1H), 4.38 (1H), 4.66 (2H), 7.21 (1H),7.48 (2H), 7.55-7.67 (3H), 8.18 (1H), 8.87 (1H).

The starting material was prepared as follows:

Example 214a Tert-butyl3-[(5-bromo-4-methoxy-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

To a solution of 1.94 g of tert-butyl3-[(tosyloxy)methyl]azetidin-1-carboxylate in 15.5 ml acetone were added837 mg of lithium iodide and the reaction mixture was stirred for 16hours at 35° C. After cooling, it was diluted with 200 ml ethyl acetateand the organic phase washed twice with 30 ml portions of water and oncewith 20 ml saturated sodium chloride solution. After drying over sodiumsulphate and filtration, this was concentrated in vacuo. In this manner,1.6 g of tert-butyl-3-(iodomethyl)azetidin-1-carboxylate were obtained,which was further reacted without purification.

To a solution of 620 mg of 5-bromo-7-methoxy-1H-indazole in 24 ml DMFwere added 1.11 g of potassium carbonate and the mixture stirred at 25°C. for 30 minutes. Then 1.25 g of the iodide prepared above was addedand the reaction mixture stirred for 3 hours at 60° C. After cooling, itwas diluted with 200 ml 1:1 tert-butyl methyl ether/hexane, washed onceeach with 20 ml portions of water and saturated sodium chloridesolution, dried over sodium sulphate and concentrated in vacuo and thecrude product thus obtained purified by column chromatography on silicagel with a hexane/ethyl acetate gradient. Yield: 263 mg of the titlecompound.

¹H-NMR (300 MHz, CDCl3): δ=1.43 (9H), 3.23 (1H), 3.78 (2H), 4.07 (2H),4.10 (3H), 4.59 (2H), 7.28 (1H), 7.36 (1H), 8.03 (1H).

Example 214b Tert-butyl3-({4-methoxy-5-[N-(2-methoxyethyl)carbamoyl]-2H-indazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1b, a total of 193 mg of the title compound wasobtained from 110 and 252 mg respectively of the compound prepared inExample 214a and 63 and 143 mg respectively of 2-methoxyethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.32 (9H), 3.10 (1H), 3.27 (3H), 3.38-3.48(4H), 3.72 (2H), 3.82-3.94 (2H), 4.17 (3H), 4.60 (2H), 7.21 (1H), 7.63(1H), 8.18 (1H), 8.87 (1H).

Example 214c2-(azetidin-3-ylmethyl)-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 50 mg of the compound prepared inExample 214b, 42 mg of the title compound was obtained, which wasfurther reacted without purification.

Example 2154-methoxy-N-(2-methoxyethyl)-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 56 mg of the title compound was obtained from42 mg of the compound prepared in Example 214c and 32 mg of4-[(trifluoromethyl)sulphany]benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=3.21 (1H), 3.27 (3H), 3.38-3.49 (4H), 3.95(1H), 4.12 (1H), 4.16 (3H), 4.21 (1H), 4.40 (1H), 4.67 (2H), 7.20 (1H),7.63 (1H), 7.69 (2H), 7.76 (2H), 8.18 (1H), 8.87 (1H).

Example 2162-{[1-(4-bromobenzoyl)azetidin-3-yl]methyl}-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 48 mg of the title compound was obtained from42 mg of the compound prepared in Example 214c and 29 mg of4-bromobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=3.23 (1H), 3.26 (3H), 3.38-3.48 (4H), 3.92(1H), 4.09 (1H), 4.16 (3H), 4.19 (1H), 4.38 (1H), 4.66 (2H), 7.20 (1H),7.51 (2H), 7.58-7.68 (3H), 8.18 (1H), 8.86 (1H).

Example 2172-{[(R)-1-(4-chlorobenzoyl)pyrrolidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 50 mg of the title compound was obtained from106 mg of the compound prepared in Example 217e and 58 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.57-1.73 (1H), 1.81-1.97 (1H), 2.47/2.51(3H), 2.78-2.93 (1H), 3.25 (3H), 3.19-3.61 (8H), 4.39/4.51 (2H),7.11-7.18 (1H), 7.33-7.43 (1H), 7.45 (2H), 7.50 (2H), 8.09-8.16 (1H),8.47/8.55 (1H).

The starting material was prepared as follows:

Example 217a(R)-tert-butyl-3-[(5-bromo-4-methyl-2H-indazol-2-yl)methyl]pyrrolidine-1-carboxylate

To a solution of 9.0 g of (R)-tert-butyl3-(hydroxymethyl)pyrrolidin-1-carboxylate in 100 ml pyridine was added12.8 g of p-toluenesulphonyl chloride at 0° C. under nitrogen andstirred for 3 hours at 25° C. The reaction mixture was diluted withethyl acetate and stirred for 30 minutes with sodium hydrogen carbonate.The phases were then separated and the organic phase washed withsaturated sodium chloride solution, dried over sodium sulphate andconcentrated in vacuo after filtration. The residue thus obtained waspurified by column chromatography on silica gel with hexane/0-100% ethylacetate. Yield: 11.4 g of(R)-tert-butyl-3-[(tosyloxy)methyl]pyrrolidin-1-carboxylate.

Analogously to Example 1c, 1.97 g of the title compound was obtainedfrom 4.53 g of 5-bromo-4-methyl-1H-indazole and 11.4 g of the(R)-tert-butyl-3-[(tosyloxy)methyl]pyrrolidin-1-carboxylate preparedabove with addition of 7.9 g of tetrabutylammonium iodide.

¹H-NMR (300 MHz, DMSO-d6): δ=1.34 (9H), 1.50-1.66 (1H), 1.81 (1H), 2.48(3H), 2.78 (1H), 3.01 (1H), 3.16 (1H), 3.25-3.37 (2H), 4.41 (2H), 7.29(1H), 7.36 (1H), 8.51 (1H).

Example 217b Methyl2-{[(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}-4-methyl-2H-indazol-5-carboxylate

Analogously to Example 1e, after two runs 820 mg of the title compoundwas obtained from 563 mg of the bromide prepared in Example 217a and0.17 ml of methanol.

¹H-NMR (300 MHz, DMSO-d6): δ=1.34 (9H), 1.58 (1H), 1.83 (1H), 2.73 (3H),2.80 (1H), 3.03 (1H), 3.17 (1H), 3.25-3.37 (2H), 3.79 (3H), 4.37-4.49(2H), 7.44 (1H), 7.64 (1H), 8.72 (1H).

Example 217c2-{[(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}-4-methyl-2H-indazol-5-carboxylicacid

Analogously to Example 1d, 701 mg of the title compound was obtainedfrom 620 mg of the ester prepared in Example 217b.

¹H-NMR (300 MHz, DMSO-d6): δ=1.34 (9H), 1.50-1.69 (1H), 1.82 (1H),1.75-1.86 (1H), 2.69-2.88 (4H), 3.03 (1H), 3.17 (1H), 3.24-3.38 (1H),4.42 (2H), 7.40 (1H), 7.65 (1H), 8.68 (1H), 12.28 (1H).

Example 217d (R)-tert-butyl3-({5-[N-(2-methoxyethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}methyl)pyrrolidin-1-carboxylate

Analogously to Example 1, 376 mg of the title compound was obtained from350 mg of the acid prepared in Example 217c and 73 mg of2-methoxyethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.35 (9H), 1.57 (1H), 1.80 (1H), 2.50 (3H),2.73-2.86 (1H), 3.01 (1H), 3.11-3.22 (1H), 3.25 (3H), 3.26-3.39 (3H),3.39-3.46 (2H), 4.42 (2H), 7.15 (1H), 7.39 (1H), 8.13 (1H), 8.52 (1H).

Example 217eN-(2-methoxyethyl)-4-methyl-2-[(R)-pyrrolidin-3-ylmethyl]-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 376 mg of the amide prepared in Example217d, 465 mg of the title compound was obtained, which was reactedwithout further purification.

Example 218 N-(2-methoxyethyl)-4-methyl-24{(R)-1-[4-(trifluoromethoxy)benzoyl]-pyrrolidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 61 mg of the title compound was obtained from106 mg of the compound prepared in Example 217e and 74 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.57-1.74 (1H), 1.81-1.97 (1H), 2.47/2.51(3H), 2.77-2.94 (1H), 3.25-3.62 (11H), 4.40/4.51 (2H), 7.09-7.19 (1H),7.31-7.44 (3H), 7.61 (2H), 8.08-8.16 (1H), 8.47/8.55 (1H).

Example 219N-(2-methoxyethyl)-4-methyl-2-({(3R)-1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]-pyrrolidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 29 mg of the title compound was obtained from106 mg of the compound prepared in Example 217e and 75 mg of4-(pentafluoro-λ⁶-sulphanyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=1.57-1.76 (1H), 1.81-1.99 (1H), 2.50 (3H),2.77-2.94 (1H), 3.16-3.62 (11H), 4.39/4.52 (2H), 7.09-7.19 (1H),7.32-7.44 (1H), 7.68 (2H), 7.90-7.97 (2H), 8.10-8.17 (1H), 8.46/8.55(1H).

Example 2202-{[(R)-1-(4-chlorobenzoyl)pyrrolidin-3-yl]methyl}-4-methyl-N-{2-[(trifluoro-methyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 29 mg of the title compound was obtained from106 mg of the compound prepared in Example 220b and 48 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.57-1.73 (1H), 1.81-1.96 (1H), 2.48/2.53(3H), 2.79-2.93 (1H), 3.13-3.60 (8H), 4.40/4.51 (2H), 7.14-7.23 (1H),7.33-7.53 (5H), 8.35-8.42 (1H), 8.49/8.58 (1H).

The starting material was prepared as follows:

Example 220a (R)-tert-butyl3-{[4-methyl-5-(N-{2-[(trifluoromethyl)sulphanyl]ethyl}-carbamoyl)-2H-indazol-2-yl]methyl}pyrrolidin-1-carboxylate

Analogously to Example 1, 245 mg of the title compound was obtained from350 mg of the acid prepared in Example 217c and 141 mg of2-[(trifluoromethyl)sulphanyl]ethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.35 (9H), 1.52-1.64 (1H), 1.81 (1H), 2.52(3H), 2.71-2.96 (2H), 2.97-3.05 (12H), 3.18 (2H), 3.23-3.28 (1H), 3.51(2H), 4.42 (2H), 7.19 (1H), 7.42 (1H), 8.39 (1H), 8.54 (1H).

Example 220b4-methyl-2-[(R)-pyrrolidin-3-ylmethyl]-N-{2-[(trifluoromethyl)sulphanyl]-ethyl}-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 245 mg of the amide prepared in Example220a, 410 mg of the title compound was obtained, which was reactedwithout further purification.

Example 2214-methyl-2-({(R)-1-[4-(trifluoromethoxy)benzoyl]pyrrolidin-3-yl}methyl)-N-{2-[(trifluoromethyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 49 mg of the title compound was obtained from106 mg of the compound prepared in Example 220b and 62 mg of4-(trifluoromethoxy)benzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.58-1.74 (1H), 1.81-1.98 (1H), 2.48/2.53(3H), 2.78-2.94 (1H), 3.12-3.62 (8H), 4.40/4.52 (2H), 7.14-7.23 (1H),7.32-7.49 (3H), 7.61 (2H), 8.35-8.43 (1H), 8.49/8.58 (1H).

Example 2222-{[(S)-1-(4-chlorobenzoyl)pyrrolidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 67 mg of the title compound was obtained from134 mg of the compound prepared in Example 222a and 73 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, CDCl3): δ=1.72-1.86 (1H), 1.99-2.20 (1H), 2.64 (3H),2.93-3.13 (1H), 3.29-3.36 (1H), 3.39 (3H), 3.45-3.71 (6H), 3.76-3.86(1H), 4.31-4.57 (2H), 6.12-6.20 (1H), 7.30-7.42 (3H), 7.43-7.56 (3H),7.90/8.02 (1H).

The starting material was prepared as follows:

Example 222a (S)-tert-butyl3-({5-[N-(2-methoxyethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}methyl)pyrrolidin-1-carboxylate

Analogously to Example 217a to 217d, this title compound was prepared ina quantity of 760 mg starting from(S)-tert-butyl-3-(hydroxymethyl)pyrrolidin-1-carboxylate.

¹H-NMR (300 MHz, DMSO-d6): δ=1.35 (9H), 1.52-1.64 (1H), 1.77-1.87 (1H),1.76-1.82 (1H), 2.50 (3H), 2.74-2.86 (1H), 3.02 (1H), 3.12-3.20 (1H),3.25 (3H), 3.31 (1H), 3.36 (2H), 3.43 (2H), 4.42 (2H), 7.16 (1H), 7.39(1H), 8.10 (1H), 8.51 (1H).

Example 222bN-(2-methoxyethyl)-4-methyl-2-[(S)-pyrrolidin-3-ylmethyl]-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 159 mg of the amide prepared in Example222a, 134 mg of the title compound was obtained, which was reactedwithout further purification.

Example 2232-({(S)-1-[(4′-fluorobiphenyl-4-yl)carbonyl]pyrrolidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 128 mg of the title compound was obtained from230 mg of the compound prepared in Example 222b and 141 mg of4′-fluorobiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, CDCl3): δ=1.73-1.89 (1H), 1.98-2.24 (1H), 2.60/2.67(3H), 2.94-3.18 (1H), 3.37/3.39 (3H), 3.49-3.76 (6H), 3.79-3.91 (2H),4.32-4.61 (2H), 6.08-6.21 (1H), 7.09-7.20 (2H), 7.28-7.38 (1H),7.46-7.62 (7H), 7.91/8.04 (1H).

Example 224N-(2-methoxyethyl)-4-methyl-2-{[(S)-1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}pyrrolidin-3-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 102 mg of the title compound was obtained from230 mg of the compound prepared in Example 222b and 184 mg of4-[4-(trifluoromethyl)phenoxy]benzoic acid.

¹H-NMR (300 MHz, CDCl3): δ=1.70-2.25 (2H), 2.63/2.66 (3H), 2.94-3.17(1H), 3.39 (3H), 3.47-3.92 (8H), 4.33-4.59 (2H), 6.15 (1H), 7.00-7.11(4H), 7.30-7.40 (1H), 7.47-7.65 (5H), 7.91/8.03 (1H).

Example 2252-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-(difluoromethoxy)-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 90 mg of the title compound was obtained from106 mg of the compound prepared in Example 225h and 49 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.14-1.58 (4H), 2.19-2.34 (1H), 2.67-2.81(1H), 2.97 (1H), 3.22-3.53 (9H), 4.37 (2H), 7.13 (1H), 7.31-7.39 (3H),7.47 (2H), 7.54 (1H), 8.21 (1H), 8.50 (1H).

The starting material was prepared as follows:

Example 225a N-[4-bromo-3-(difluoromethoxy)-2-methylphenyl]acetamide

To a solution of 5.0 g of 3-difluoromethoxy-2-methylaniline in 48 mlDMF, a solution of 5.1 g of N-bromosuccinimide in 24 ml DMF was addeddropwise at 0° C. and stirred for 1 hour at 0° C. Then the reactionmixture was diluted with 400 ml hexane/ethyl acetate, and washed oncewith 50 ml of a 10% aqueous sodium carbonate solution and three timeswith 50 ml portions of water. After drying over sodium sulphate andfiltration, this was concentrated in vacuo. The crude product thusobtained (6.68 g) was used in the next step without purification.

To a solution of 6.39 g of the bromide prepared above in 70 ml pyridine,3.0 ml of acetic anhydride were added dropwise at 0° C. and stirred for20 hours at 25° C. The reaction mixture was concentrated in vacuo andthe crude product thus obtained purified by column chromatography onsilica gel with hexane/0-100% ethyl acetate. The substance was thenrecrystallized from hexane. In this manner, 6.39 g of the title compoundwas obtained.

¹H-NMR (300 MHz, CDCl3): δ=2.22 (3H), 2.27 (3H), 6.51 (1H), 6.95 (1H),7.46 (1H), 7.71 (1H).

Example 225b 1-[5-bromo-4-(difluoromethoxy)-1H-indazol-1-yl]ethan-1-one

Analogously to Example 212c, 5.32 g of the title compound was obtainedfrom 6.38 g of the amide prepared in Example 225a.

¹H-NMR (300 MHz, DMSO-d6): δ=2.70 (3H), 7.34 (1H), 7.90 (1H), 8.16 (1H),8.46 (1H).

Example 225c 5-bromo-4-(difluoromethoxy)-1H-indazole

Analogously to Example 212d, 4.12 g of the title compound was obtainedfrom 5.32 g of the indazole prepared in Example 225b.

¹H-NMR (300 MHz, DMSO-d6): δ=7.30 (1H), 7.44 (1H), 7.56 (1H), 8.06 (1H),13.54 (1H).

Example 225d Tert-butyl4-{[5-bromo-4-(difluoromethoxy)-2H-indazol-2-yl]methyl}-piperidin-1-carboxylate

Analogously to Example 212e, 2.06 g of the title compound was obtainedfrom 4.1 g of the indazole prepared in Example 225c and 8.7 g oftert-butyl 4-[(tosyloxy)methyl]piperidin-1-carboxylate.

¹H-NMR (300 MHz, CDCl3): δ=1.19-1.28 (2H), 1.45 (9H), 1.51-1.59 (2H),2.25 (1H), 2.68 (2H), 4.12 (2H), 4.27 (2H), 6.61 (1H), 7.41 (1H), 7.50(1H), 7.95 (1H).

Example 225e Methyl2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-4-(difluoromethoxy)-2H-indazol-5-carboxylate

Analogously to Example 1e, after three runs 1.28 g of the title compoundwas obtained from 683 mg of the bromide prepared in Example 225d and0.18 ml of methanol.

¹H-NMR (300 MHz, DMSO-d6): δ=0.96-1.22 (2H), 1.28-1.47 (11H), 2.14 (1H),2.54-2.74 (2H), 3.81 (3H), 3.87 (2H), 4.36 (2H), 7.17 (1H), 7.58 (1H),7.65 (1H), 8.62 (1H).

Example 225f2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-4-(difluoromethoxy)-2H-indazol-5-carboxylicacid

Analogously to Example 1d, 1.05 g of the title compound was obtainedfrom 1.28 g of the ester prepared in Example 225e.

¹H-NMR (300 MHz, DMSO-d6): δ=0.97-1.16 (2H), 1.28-1.47 (11H), 2.13 (1H),2.63 (2H), 3.87 (2H), 4.35 (2H), 7.14 (1H), 7.54 (1H), 7.65 (1H), 8.58(1H), 13.05 (1H).

Example 225g Tert-butyl4-({4-(difluoromethoxy)-5-[N-(2-methoxyethyl)carbamoyl]-2H-indazol-2-yl}methyl)piperidin-1-carboxylate

Analogously to Example 1, 503 mg of the title compound was obtained from520 mg of the compound prepared in Example 225f and 92 mg of2-methoxyethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.01-1.13 (2H), 1.34 (9H), 1.38 (2H), 2.13(1H), 2.59-2.71 (6H), 3.24 (3H), 3.34-3.44 (2H), 3.87 (2H), 4.34 (2H),7.14 (1H), 7.33 (1H), 7.54 (1H), 8.21 (1H), 8.50 (1H).

Example 225h4-(difluoromethoxy)-N-(2-methoxyethyl)-2-(4-piperidylmethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 122 mg of the amide prepared in Example225g, 106 mg of the title compound was obtained, which was reactedwithout further purification.

Example 2264-(difluoromethoxy)-2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 11 mg of the title compound was obtained from106 mg of the compound prepared in Example 225h and 59 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=1.10-1.59 (4H), 2.23-2.33 (1H), 2.75-3.01(2H), 3.24 (3H), 3.33-3.51 (5H), 3.51-3.72 (1H), 4.37 (2H), 6.95 (2H),7.07-7.12 (2H), 7.13 (1H), 7.17-7.26 (2H), 7.28-7.39 (3H), 7.54 (1H),8.21 (1H), 8.50 (1H).

Example 2274-(difluoromethoxy)-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 38 mg of the title compound was obtained from106 mg of the compound prepared in Example 225h and 55 mg of4′-fluorobiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=1.14-1.62 (4H), 2.23-2.35 (1H), 2.68-2.85(1H), 2.91-3.09 (1H), 3.24 (3H), 3.32-3.48 (5H), 3.50-3.70 (1H), 4.38(2H), 7.14 (1H), 7.28 (2H), 7.33 (1H), 7.40 (2H), 7.55 (1H), 7.64-7.75(4H), 8.21 (1H), 8.51 (1H).

Example 2282-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-4-(difluoromethoxy)-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 75 mg of the title compound was obtained from106 mg of the compound prepared in Example 225h and 41 mg of4-cyclopropylbenzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=0.66 (2H), 0.94 (2H), 1.10-1.54 (4H), 1.90(1H), 2.14-2.31 (1H), 2.72-3.02 (2H), 3.03-3.18 (1H), 3.24 (3H),3.33-3.47 (4H), 3.49-3.68 (1H), 4.37 (2H), 7.07 (2H), 7.13 (1H), 7.19(2H), 7.33 (1H), 7.54 (1H), 8.21 (1H), 8.50 (1H).

Example 2292-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)-ethyl]-4-(difluoromethoxy)-2H-indazole-5-carboxamide

Analogously to Example 55, 170 mg of the title compound was obtainedfrom 127 mg of the compound prepared in Example 229b and 53 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=0.14 (2H), 0.42 (2H), 0.96 (1H), 1.10-1.27(2H), 1.37 (1H), 1.51 (1H), 2.26 (1H), 2.71 (1H), 2.97 (1H), 3.20-3.55(8H), 4.37 (2H), 7.14 (1H), 7.31-7.38 (3H), 7.47 (2H), 7.55 (1H), 8.21(1H), 8.51 (1H).

The starting material was prepared as follows:

Example 229a Tert-butyl4-{[5-{N-[2-(cyclopropylmethoxy)ethyl]carbamoyl}-4-(difluoromethoxy)-2H-indazol-2-yl]methyl}piperidin-1-carboxylate

Analogously to Example 1, 453 mg of the title compound was obtained from520 mg of the compound prepared in Example 225f and 185 mg of2-(cyclopropylmethoxy)ethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=0.14 (2H), 0.42 (2H), 0.97 (1H), 1.07 (2H),1.34 (9H), 1.39 (2H), 2.13 (1H), 2.56-2.72 (2H), 3.23 (2H), 3.37 (2H),3.48 (2H), 3.87 (2H), 4.34 (2H), 7.15 (1H), 7.34 (1H), 7.55 (1H), 8.21(1H), 8.50 (1H).

Example 229bN-[(2-cyclopropylmethoxy)ethyl]-4-(difluoromethoxy)-2-(4-piperidylmethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 145 mg of the amide prepared in Example229a, 127 mg of the title compound was obtained, which was reactedwithout further purification.

Example 230N-[2-(cyclopropylmethoxy)ethyl]-4-(difluoromethoxy)-2-({1-[4-(4-fluoro-phenoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 156 mg of the title compound was obtained from127 mg of the compound prepared in Example 229b and 64 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=0.14 (2H), 0.42 (2H), 0.96 (1H), 1.10-1.54(4H), 2.18-2.33 (1H), 2.71-3.02 (2H), 3.03-3.16 (1H), 3.22 (2H), 3.37(2H), 3.47 (2H), 3.55-3.68 (1H), 4.37 (2H), 6.95 (2H), 7.10 (2H), 7.14(1H), 7.22 (2H), 7.34 (3H), 7.55 (1H), 8.21 (1H), 8.51 (1H).

Example 231N-[2-(cyclopropylmethoxy)ethyl]-4-(difluoromethoxy)-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 164 mg of the title compound was obtained from127 mg of the compound prepared in Example 229b and 60 mg of4′-fluorobiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=0.14 (2H), 0.42 (2H), 0.96 (1H), 1.14-1.60(4H), 2.27 (1H), 2.70-3.04 (1H), 2.87 (1H), 3.03-3.15 (1H), 3.22 (2H),3.37 (2H), 3.47 (2H), 3.60 (1H), 4.38 (2H), 7.14 (1H), 7.28 (2H), 7.34(1H), 7.41 (2H), 7.55 (1H), 7.64-7.75 (4H), 8.21 (1H), 8.52 (1H).

Example 2322-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-(2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 55, 113 mg of the title compound was obtainedfrom 109 mg of the compound prepared in Example 232h and 46 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.12-1.61 (3H), 2.19-2.34 (1H), 2.67-3.07(2H), 3.23 (3H), 3.33-3.56 (4H), 4.28-4.47 (3H), 4.95 (2H), 7.31-7.39(3H), 7.40-7.50 (3H), 7.99 (1H), 8.65 (1H).

The starting material was prepared as follows:

Example 232aN-[4-bromo-2-methyl-3-(2,2,2-trifluoroethoxy)phenyl]acetamide

Analogously to Example 225a, 6.13 g of the title compound was obtainedfrom 5.0 g of 2-methyl-3-(2,2,2-trifluoroethoxy)aniline

¹H-NMR (300 MHz, DMSO-d6): δ=2.07 (3H), 2.18 (3H), 4.55 (2H), 7.29 (1H),7.45 (1H), 9.42 (1H).

Example 232b1-[5-bromo-4-(2,2,2-trifluoroethoxy)-1H-indazol-1-yl]ethan-1-one

Analogously to Example 212c, 5.08 g of the title compound was obtainedfrom 6.13 g of the amide prepared in Example 232a.

¹H-NMR (300 MHz, DMSO-d6): δ=2.69 (3H), 5.14 (2H), 7.80 (1H), 7.99 (1H),8.64 (1H).

Example 232c 5-bromo-4-(2,2,2-trifluoroethoxy)-1H-indazole

Analogously to Example 212d, 3.57 g of the title compound was obtainedfrom 5.08 g of the indazole prepared in Example 232b.

¹H-NMR (300 MHz, DMSO-d6): δ=5.05 (2H), 7.24 (1H), 7.45 (1H), 8.26 (1H),13.38 (1H).

Example 232d Tert-butyl4-{[5-bromo-4-(2,2,2-trifluoroethoxy)-2H-indazol-2-yl]methyl}-piperidin-1-carboxylate

Analogously to Example 212e, 1.77 g of the title compound was obtainedfrom 3.57 g of the indazole prepared in Example 232c and 6.7 g oftert-butyl 4-[(tosyloxy)methyl]piperidin-1-carboxylate.

¹H-NMR (300 MHz, CDCl3): δ=1.16-1.31 (2H), 1.45 (9H), 1.54 (2H), 2.25(1H), 2.68 (2H), 4.05-4.21 (2H), 4.27 (2H), 4.54 (2H), 7.35 (1H), 7.41(1H), 7.91 (1H).

Example 232e Methyl2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-4-(2,2,2-trifluoro-ethoxy)-2H-indazole-5-carboxylate

Analogously to Example 1e, after three runs 857 mg of the title compoundwas obtained from 590 mg of the bromide prepared in Example 232d and0.15 ml of methanol.

¹H-NMR (300 MHz, DMSO-d6): δ=1.00-1.17 (2H), 1.34 (9H), 1.37-1.47 (2H),2.13 (1H), 2.55-2.74 (2H), 3.79 (3H), 3.87 (2H), 4.32 (2H), 4.89 (2H),7.39 (1H), 7.56 (1H), 8.67 (1H).

Example 232f2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-4-(2,2,2-trifluoroethoxy)-2H-indazole-5-carboxylicacid

Analogously to Example 1d, 724 mg of the title compound was obtainedfrom 854 mg of the ester prepared in Example 232e.

¹H-NMR (300 MHz, DMSO-d6): δ=1.01-1.17 (2H), 1.34 (9H), 1.40 (2H), 2.13(1H), 2.53-2.75 (2H), 3.87 (2H), 4.32 (2H), 4.84 (2H), 7.37 (1H), 7.58(1H), 8.60 (1H), 12.74 (1H).

Example 232g Tert-butyl4-({5-[N-(2-methoxyethyl)carbamoyl]-4-(2,2,2-trifluoroethoxy)-2H-indazol-2-yl}methyl)piperidin-1-carboxylate

Analogously to Example 1, 386 mg of the title compound was obtained from360 mg of the compound prepared in Example 232f and 59 mg of2-methoxyethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=0.98-1.18 (2H), 1.34 (9H), 1.43 (2H), 2.14(1H), 2.65 (2H), 3.23 (3H), 3.35-3.47 (4H), 3.88 (2H), 4.30 (2H), 4.96(2H), 7.35 (1H), 7.43 (1H), 7.99 (1H), 8.65 (1H).

Example 232hN-(2-methoxyethyl)-2-(4-piperidylmethyl)-4-(2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 109 mg of the amide prepared in Example232g, 113 mg of the title compound was obtained, which was reactedwithout further purification.

Example 2332-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-(2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 1, 51 mg of the title compound was obtained from109 mg of the compound prepared in Example 232h and 56 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=1.10-1.31 (1H), 1.48 (2H), 2.18-2.37 (1H),2.69-3.04 (2H), 3.23 (3H), 3.37-3.48 (4H), 3.56-3.71 (1H), 4.33 (2H),4.95 (2H), 6.95 (2H), 7.06-7.15 (2H), 7.18-7.27 (2H), 7.31-7.38 (3H),7.40-7.47 (1H), 7.99 (1H), 8.66 (1H).

Example 2342-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-(2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 1, 61 mg of the title compound was obtained from109 mg of the compound prepared in Example 232h and 52 mg of4-(4-fluorophenyl)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=1.14-1.63 (3H), 2.19-2.37 (1H), 2.68-3.09(2H), 3.23 (3H), 3.34-3.48 (4H), 3.62 (1H), 4.28-4.42 (2H), 4.96 (2H),7.22-7.47 (6H), 7.64-7.76 (4H), 7.99 (1H), 8.66 (1H).

Example 2352-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)-ethyl]-4-(2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 55, 122 mg of the title compound was obtainedfrom 122 mg of the compound prepared in Example 235b and 48 mg of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=0.13 (2H), 0.41 (2H), 0.95 (1H), 1.11-1.62(3H), 2.19-2.34 (1H), 2.73 (1H), 2.98 (1H), 3.21 (2H), 3.33-3.57 (5H),4.33 (2H), 4.95 (2H), 7.31-7.51 (6H), 8.00 (1H), 8.65 (1H).

The starting material was prepared as follows:

Example 235a Tert-butyl4-{[5-{N-[2-(cyclopropylmethoxy)ethyl]carbamoyl}-4-(2,2,2-trifluoroethoxy)-2H-indazol-2-yl]methyl}piperidin-1-carboxylate

Analogously to Example 1, 429 mg of the title compound was obtained from360 mg of the compound prepared in Example 232f and 119 mg of2-(cyclopropylmethoxy)ethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=0.13 (2H), 0.42 (2H), 0.95 (1H), 1.08 (2H),1.34 (9H), 1.41 (2H), 2.14 (1H), 3.22 (2H), 3.41 (2H), 3.48 (2H), 3.88(2H), 4.30 (2H), 4.95 (2H), 7.35 (1H), 7.42 (1H), 8.00 (1H), 8.65 (1H).

Example 235bN-[2-(cyclopropylmethoxy)ethyl]-2-(4-piperidylmethyl)-4-(2,2,2-trifluoro-ethoxy)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 138 mg of the amide prepared in Example235a, 122 mg of the title compound was obtained, which was reactedwithout further purification.

Example 236N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-(2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 1, 95 mg of the title compound was obtained from122 mg of the compound prepared in Example 235b and 58 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=0.13 (2H), 0.41 (2H), 0.95 (1H), 1.09-1.60(3H), 2.17-2.36 (1H), 2.68-3.06 (2H), 3.22 (2H), 3.34-3.76 (5H), 4.33(2H), 4.95 (2H), 6.95 (2H), 7.06-7.14 (2H), 7.17-7.27 (2H), 7.30-7.38(3H), 7.42 (1H), 7.99 (1H), 8.65 (1H).

Example 237N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-(2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 1, 98 mg of the title compound was obtained from122 mg of the compound prepared in Example 235b and 54 mg of4-(4-fluorophenoxy)benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=0.12 (2H), 0.41 (2H), 0.95 (1H), 1.15-1.64(3H), 2.21-2.36 (1H), 2.70-3.10 (2H), 3.21 (2H), 3.35-3.69 (5H), 4.35(2H), 4.95 (2H), 7.22-7.46 (6H), 7.63-7.77 (4H), 7.99 (1H), 8.66 (1H).

Example 2382-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-[2-(3-methoxyazetidin-1-yl)ethyl]-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 33 mg of the title compound was obtained from120 mg of the compound prepared in Example 238c and 40 mg of2-(3-methoxyazetidin-1-yl)ethylamine (prepared analogously toWO2006/104406).

¹H-NMR (300 MHz, CDCl3): δ=0.83 (1H), 1.20-2.01 (4H), 2.38 (1H), 2.66(3H), 2.69-3.09 (2H), 3.31 (3H), 3.43 (2H), 3.56-3.90 (5H), 4.18-4.32(3H), 4.43 (2H), 6.91 (1H), 7.30-7.41 (5H), 7.52 (1H), 7.95 (1H).

The starting material was prepared as follows:

Example 238a methyl4-methyl-2-(4-piperidylmethyl)-2H-indazol-5-carboxylate hydrochloride

Analogously to Example 1a, from 3.0 g of the ester prepared in Example1e, 2.51 g of the title compound was obtained, which was reacted withoutfurther purification.

Example 238b Methyl2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-2H-indazol-5-carboxylate

Analogously to Example 55, 3.27 g of the title compound was obtainedfrom 2.5 g of the compound prepared in Example 238a and 1.5 g of4-chlorobenzoyl chloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.16-1.63 (4H), 2.21-2.33 (1H), 2.73 (4H),2.90-3.05 (1H), 3.44-3.55 (1H), 3.79 (3H), 4.32 (2H), 4.36-4.47 (1H),7.36 (2H), 7.42 (1H), 7.46 (2H), 7.63 (1H), 8.67 (1H).

Example 238c2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-2H-indazol-5-carboxylicacid

Analogously to Example 1d, 470 mg of the title compound was obtainedfrom 485 mg of the ester prepared in Example 238b.

Example 239(+/−)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 188 mg of the title compound was obtained from300 mg of the compound prepared in Example 238c and 92 mg of3,4,5,6-tetrahydro-2H-pyran-2-ylmethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.01-1.27 (3H), 1.29-1.64 (7H), 2.19-2.32(1H), 2.48 (3H), 2.66-2.80 (1H), 2.89-3.00 (1H), 3.00-3.08 (1H),3.16-3.25 (2H), 3.34-3.42 (1H), 3.43-3.55 (1H), 3.77-3.88 (1H), 4.31(2H), 4.39 (1H), 7.14 (1H), 7.32-7.40 (2H), 7.46 (2H), 7.83 (1H), 8.09(1H), 8.46 (1H).

Example 240 (R orS)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole-5-carboxamide

From 185 mg of the racemate prepared in Example 239, 51 mg of the titlecompound together with 53 mg of the slower-eluting enantiomer (Example241) were obtained by racemate separation by means of preparative chiralHPLC (Method B).

Analytical chiral HPLC: 7.02 min.

Example 241 (S orR)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole-5-carboxamide

From 185 mg of the racemate prepared in Example 239, 53 mg of the titlecompound together with 51 mg of the faster-eluting enantiomer (Example240) were obtained by racemate separation by means of preparative chiralHPLC (Method B).

Analytical chiral HPLC: 8.24 min.

Example 2422-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-ethyl-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 85 mg of the title compound was obtained from300 mg of the compound prepared in Example 238c and 43 mg of ethylamine2M in THF.

¹H-NMR (300 MHz, DMSO-d6): δ=1.08 (3H), 1.16-1.60 (4H), 2.20-2.33 (1H),2.48 (3H), 2.63-3.07 (2H), 3.22 (2H), 3.48 (1H), 4.24-4.46 (3H), 7.14(1H), 7.31-7.42 (3H), 7.46 (2H), 8.08 (1H), 8.46 (1H).

Example 2432-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-isobutyl-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 92 mg of the title compound was obtained from300 mg of the compound prepared in Example 238c and 69 mg ofisobutylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=0.85-0.90 (6H), 1.13-1.57 (4H), 1.75-1.83(1H), 2.21-2.34 (1H), 2.49 (3H), 3.03 (4H), 3.48 (1H), 4.27-4.45 (3H),7.14 (1H), 7.31-7.41 (3H), 7.46 (2H), 8.11 (1H), 8.47 (1H).

Example 2442-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-mesylethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 132 mg of the title compound was obtained from300 mg of the compound prepared in Example 238c and 151 mg of2-mesylethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.19-1.62 (4H), 2.24-2.36 (1H), 2.54 (3H),2.70-3.05 (2H), 3.05 (3H), 3.38 (2H), 3.52 (1H), 3.65 (2H), 4.30-4.49(3H), 7.22 (1H), 7.38 (2H), 7.42 (1H), 7.49 (2H), 8.33 (1H), 8.52 (1H).

Example 245N-(2-mesylethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 67 mg of the title compound was obtained from137 mg of the compound prepared in Example 245b and 41 mg of2-mesylethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.15-1.62 (4H), 2.22-2.33 (1H), 2.50 (3H),2.68-3.01 (2H), 3.02 (2H), 3.35 (1H), 3.52-3.69 (3H), 4.28-4.47 (2H),7.12 (1H), 7.15-7.22 (2H), 7.37-7.44 (2H), 7.73 (1H), 8.32 (1H), 8.50(1H).

The starting material was prepared as follows:

Example 245a Methyl4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazol-5-carboxylate

Analogously to Example 1, 2.73 g of the title compound was obtained from3.76 g of the compound prepared in Example 238a and 3.28 g of4-[4-(trifluoromethyl)phenoxy]benzoic acid.

¹H-NMR (300 MHz, DMSO-d6): δ=1.25 (2H), 1.35-1.70 (2H), 2.20-2.37 (1H),2.65-2.70 (3H), 2.75-3.10 (2H), 3.52-3.72 (1H), 3.82 (4H), 4.36 (2H),7.14 (2H), 7.20 (2H), 7.39-7.48 (3H), 7.66 (1H), 7.75 (2H), 8.70 (1H).

Example 245b4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)-methyl]-2H-indazol-5-carboxylicacid

Analogously to Example 1d, 1.1 g of the title compound was obtained from2.73 g of the ester prepared in Example 245a.

Example 246N-(2-cyanoethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 144 mg of the title compound was obtained from137 mg of the compound prepared in Example 245b and 18 mg of3-aminopropanenitrile.

¹H-NMR (300 MHz, DMSO-d6): δ=1.13-1.58 (4H), 2.21-2.33 (1H), 2.52 (3H),2.75 (2H), 2.80-3.16 (2H), 3.44 (2H), 3.59 (1H), 4.27-4.50 (3H), 7.12(2H), 7.15-7.21 (3H), 7.37-7.44 (3H), 7.73 (2H), 8.46 (1H), 8.51 (1H)

Example 247N-(cyanomethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 125 mg of the title compound was obtained from137 mg of the compound prepared in Example 245b and 24 mg of2-aminoacetonitrile hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.16-1.60 (4H), 2.23-2.34 (1H), 2.53 (3H),2.69-3.06 (2H), 3.59 (1H), 4.26 (2H), 4.29-4.50 (3H), 7.08-7.23 (5H),7.38-7.46 (3H), 7.73 (2H), 8.54 (1H), 8.83 (1H).

Example 248(+/−)-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 231 mg of the title compound was obtained from254 mg of the compound prepared in Example 245b and 72 mg of3,4,5,6-tetrahydro-2H-pyran-2-ylmethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.01-1.66 (10H), 2.24-2.32 (1H), 2.70-3.15(4H), 3.21 (3H), 3.34-3.43 (1H), 3.54-3.64 (1H), 3.76-3.89 (2H), 4.32(3H), 7.09-7.21 (5H), 7.35-7.44 (3H), 7.73 (2H), 8.09 (1H), 8.47 (1H).

Example 249(+/−)-N-(1,4-dioxan-2-ylmethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 280 mg of the title compound was obtained from254 mg of the compound prepared in Example 245b and 73 mg of1,4-dioxan-2-ylmethylamine.

¹H-NMR (300 MHz, DMSO-d6): δ=1.13-1.61 (4H), 2.23-2.32 (1H), 2.49 (3H),2.75 (1H), 2.94-3.27 (4H), 3.38-3.77 (8H), 4.32 (2H), 7.09-7.21 (5H),7.36-7.44 (3H), 7.73 (2H), 8.16 (1H), 8.48 (1H).

Example 2502-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(cyclobutylmethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 79 mg of the title compound was obtained from300 mg of the compound prepared in Example 238c and 115 mg ofcyclobutylmethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d6): δ=1.16-1.58 (4H), 1.64-1.86 (4H), 1.90-2.01(2H), 2.19-2.32 (1H), 2.48 (3H), 2.50 (1H), 2.66-3.05 (2H), 3.19-3.25(2H), 3.48 (1H), 4.27-4.47 (3H), 7.12 (1H), 7.31-7.40 (3H), 7.46 (2H),8.09 (1H), 8.46 (1H).

Example 2512-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2,2-dimethylpropyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 108 mg of the title compound was obtained from300 mg of the compound prepared in Example 238c and 83 mg of2,2-dimethylpropan-1-amine

¹H-NMR (300 MHz, DMSO-d6): δ=0.91 (9H), 1.17-1.63 (4H), 2.24-2.36 (1H),2.52 (3H), 2.70-3.04 (2H), 3.07 (2H), 3.52 (1H), 4.30-4.50 (3H), 7.17(1H), 7.38 (2H), 7.42 (1H), 7.49 (2H), 8.07 (1H), 8.49 (1H).

Example 2522-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-hydroxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 84 mg of the title compound was obtained from370 mg of the compound prepared in Example 238c and 54 mg of2-aminoethanol.

¹H-NMR (300 MHz, DMSO-d6): δ=1.14-1.64 (4H), 2.24-2.35 (1H), 2.53 (3H),2.69-3.09 (2H), 3.30 (2H), 3.43-3.58 (3H), 4.27-4.50 (3H), 4.67 (1H),7.20 (1H), 7.35-7.43 (3H), 7.49 (2H), 8.02 (1H), 8.49 (1H).

Example 2532-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(3-hydroxypropyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 95 mg of the title compound was obtained from370 mg of the compound prepared in Example 238c and 66 mg of3-aminopropan-1-ol.

¹H-NMR (300 MHz, DMSO-d6): δ=1.17-1.60 (4H), 1.66 (2H), 2.22-2.35 (1H),2.53 (3H), 2.70-3.09 (2H), 3.27 (2H), 3.47 (2H), 3.47-3.67 (1H), 4.34(2H), 4.41 (1H), 4.45 (1H), 7.17 (1H), 7.35-7.43 (3H), 7.49 (2H), 8.07(1H), 8.49 (1H).

Example 2544-methoxy-N-(2-methoxyethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 90 mg of the title compound was obtained from100 mg of the compound prepared in Example 214c and 97 mg of4-(trifluoromethoxy)benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 3.24-3.29 (1H), 3.29-3.32 (3H),3.43-3.51 (4H), 3.91-4.04 (1H), 4.10-4.18 (1H), 4.20 (3H), 4.22-4.29(1H), 4.44 (1H), 4.70 (2H), 7.24 (1H), 7.37-7.51 (2H), 7.66 (1H),7.70-7.80 (2H), 8.22 (1H), 8.91 (1H).

Example 2552-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 40 mg of the title compound was obtained from100 mg of the compound prepared in Example 214c and 98 mg of2-fluoro-4-(trifluoromethyl)benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=3.30 (4H), 3.44-3.50 (4H), 3.94-4.04(2H), 4.15 (2H), 4.20 (3H), 4.70 (2H), 7.24 (1H), 7.60-7.75 (3H),7.78-7.89 (1H), 8.16-8.27 (1H), 8.90 (1H).

Example 2562-({1-[4-chloro-3-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 40 mg of the title compound was obtained from100 mg of the compound prepared in Example 214c and 106 mg of4-chloro-3-(trifluoromethyl)benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 3.30 (4H), 3.43-3.53 (4H), 3.95-4.05(1H), 4.20 (4H), 4.23-4.31 (1H), 4.47 (1H), 4.71 (2H), 7.23 (1H), 7.67(1H), 7.78-7.85 (1H), 7.86-7.93 (1H), 7.96 (1H), 8.22 (1H), 8.90 (1H).

Example 2572-{[1-(4-chloro-2-fluorobenzoyl)azetidin-3-yl]methyl}-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 20 mg of the title compound was obtained from100 mg of the compound prepared in Example 214c and 82 mg of4-chloro-2-fluorobenzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 3.30 (4H), 3.42-3.51 (4H), 3.98(2H), 4.14 (2H), 4.20 (3H), 4.69 (2H), 7.24 (1H), 7.38 (1H), 7.48 (1H),7.56 (1H), 7.66 (1H), 8.15-8.30 (1H), 8.90 (1H).

Example 2582-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methoxy-N-(2-morpholinoethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b Version B, 67 mg of the title compound wasobtained from 66 mg of the compound prepared in Example 258d and 32 mgof 2-morpholinoethylamine in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 2.44 (4H), 3.21-3.36 (3H), 3.42(2H), 3.61 (4H), 3.88-4.04 (1H), 4.07-4.18 (1H), 4.23 (4H), 4.35-4.50(1H), 4.70 (2H), 7.25 (1H), 7.41-7.56 (2H), 7.59-7.66 (2H), 7.70 (1H),8.32 (1H), 8.91 (1H).

The starting material was prepared as follows:

Example 258a Methyl2-{[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}-4-methoxy-2H-indazol-5-carboxylate

Analogously to Example 1e, 448 mg of the title compound was obtainedfrom 750 mg of the compound prepared in Example 214a and 546 mg ofmethanol.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.27-1.44 (9H), 3.01-3.22 (1H), 3.78(5H), 3.85-3.99 (2H), 4.14 (3H), 4.64 (2H), 7.24 (1H), 7.51 (1H), 8.94(1H).

Example 258b Methyl2-(azetidin-3-ylmethyl)-4-methoxy-2H-indazol-5-carboxylate

800 mg of 258a were first placed in 40 ml acetone, treated with 40 ml ofsemiconcentrated hydrochloric acid, stirred until complete conversionand concentrated to dryness. Yield: 414 mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 3.39 (1H), 3.79 (3H), 3.84-3.95(2H), 3.96-4.07 (2H), 4.15 (3H), 4.72 (2H), 7.25 (1H), 7.52 (1H), 8.92(1H).

Example 258c Methyl2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methoxy-2H-indazol-5-carboxylate

404 mg of 258b were first placed in 30 ml DCM at 0° C., treated with0.21 ml of 4-chlorobenzoyl chloride and 0.75 ml ofN-ethyldiisopropylamine and stirred at room temperature until completeconversion. For the work-up, the reaction solution was treated withsaturated sodium hydrogen carbonate solution, extracted with DCM and thecombined organic phases dried with sodium sulphate and concentrated todryness. This yielded 608 mg of the title compound, which was used inthe next step without further purification.

Example 258d2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methoxy-2H-indazol-5-carboxylicacid

550 mg of 258c were first placed in 20 ml ethanol, treated with 20 ml of2N sodium hydroxide and stirred until complete conversion. For thework-up, the reaction solution was adjusted to a pH of 3 with 1Nhydrochloric acid, extracted with ethyl acetate, and the combinedorganic phases dried with sodium sulphate and concentrated to dryness.Yield after purification by column chromatography on silica gel with ahexane/ethyl acetate gradient: 213 mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 3.27 (1H), 3.97 (1H), 4.07-4.17(4H), 4.24 (1H), 4.42 (1H), 4.70 (2H), 7.22 (1H), 7.46-7.57 (3H),7.59-7.68 (2H), 8.88 (1H), 12.61 (m, 1H).

Example 2592-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-ethoxyethyl)-4-methoxy-2H-indazole-5-carboxamide

Analogously to Example 1b Version B, 30 mg of the title compound wasobtained from 66 mg of the compound prepared in Example 258d and 22 mgof 2-ethoxyethylamine in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.07-1.21 (3H), 3.30 (1H), 3.40-3.57(6H), 3.90-4.02 (1H), 4.08-4.17 (1H), 4.21 (4H), 4.34-4.48 (1H), 4.70(2H), 7.24 (1H), 7.45-7.57 (2H), 7.60-7.74 (3H), 8.24 (1H), 8.91 (1H).

Example 2602-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-methoxy-2H-indazole-5-carboxamide

Analogously to Example 1b Version B, 58 mg of the title compound wasobtained from 66 mg of the compound prepared in Example 258d and 37 mgof 2-(3,3-difluoropyrrolidin-1-yl)ethylamine in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 2.27 (2H), 2.64 (2H), 2.77 (2H),2.96 (2H), 3.22-3.30 (1H), 3.41 (2H), 3.92-4.01 (1H), 4.11 (1H), 4.19(4H), 4.35-4.48 (1H), 4.70 (2H), 7.24 (1H), 7.51 (2H), 7.57-7.75 (3H),8.32 (1H), 8.90 (1H).

Example 2612-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methoxy-N-(2-morpholinoethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 77 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 261e and 46 mgof 2-morpholinoethylamine in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.11-1.33 (2H), 1.35-1.75 (2H),2.18-2.39 (1H), 2.65-2.88 (2H), 2.90-3.23 (3H), 3.41-3.82 (8H),3.84-4.12 (2H), 4.24 (3H), 4.35 (3H), 7.26 (1H), 7.33-7.44 (2H),7.46-7.58 (2H), 7.69 (1H), 8.27-8.52 (1H), 8.87 (1H).

The starting material was prepared as follows:

Example 261a Tert-butyl4-[(5-bromo-4-methoxy-2H-indazol-2-yl)methyl]piperidin-1-carboxylate

Analogously to Example 1c, 5.57 g of the title compound was obtainedfrom 9.65 g of 5-bromo-4-methoxy-1H-indazole and 23.55 g oftert-butyl-4-[(tosyloxy)methyl]piperidin-1-carboxylate.

¹H-NMR (400 MHz, chloroform-d): δ [ppm], 1.16-1.31 (2H), 1.39-1.49 (9H),1.52-1.64 (2H), 2.16-2.36 (1H), 2.56-2.80 (2H), 4.11 (5H), 4.26 (2H),7.28-7.33 (1H), 7.34-7.39 (1H), 7.99 (1H).

Example 261b Methyl2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-4-methoxy-2H-indazol-5-carboxylate

Analogously to Example 1e, 1.1 g of the title compound was obtained from2.4 g of the compound prepared in Example 261a and 1.63 g of methanol.

Example 261c Methyl4-methoxy-2-(4-piperidylmethyl)-2H-indazol-5-carboxylate

Analogously to Example 258b, from 1.1 g of the compound prepared inExample 261b 1.1 g of the title compound was obtained, which was reactedin the next step without further purification.

Example 261d Methyl2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methoxy-2H-indazol-5-carboxylate

Analogously to Example 258c, from 1.1 g of the compound prepared inExample 261c and 762 mg of 4-chlorobenzoyl chloride, 980 mg of the titlecompound was obtained after purification by column chromatography onsilica gel with a hexane/ethyl acetate gradient.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.24 (2H), 1.36-1.76 (2H), 2.18-2.40(1H), 2.65-2.88 (1H), 2.91-3.12 (1H), 3.42-3.67 (1H), 3.78 (3H),4.05-4.21 (3H), 4.35 (3H), 7.24 (1H), 7.34-7.43 (2H), 7.45-7.56 (3H),8.86 (1H).

Example 261e2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methoxy-2H-indazol-5-carboxylicacid

Analogously to Example 258d, 547 mg of the title compound was obtainedfrom 980 mg of the compound prepared in Example 261d.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.12-1.35 (2H), 1.35-1.73 (2H),2.21-2.40 (1H), 2.63-3.12 (2H), 3.14-3.70 (3H), 4.34 (3H), 5.76 (s, 1H),7.21 (1H), 7.32-7.45 (2H), 7.46-7.58 (3H), 8.76 (1H).

Example 2622-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 50 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 261e and 26 mgof 2-methoxyethylamine in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.11-1.35 (2H), 1.35-1.72 (2H),2.21-2.39 (1H), 2.69-2.88 (1H), 2.92-3.11 (1H), 3.30 (s, 3H), 3.38-3.64(5H), 4.20 (3H), 4.34 (3H), 7.25 (1H), 7.34-7.43 (2H), 7.45-7.57 (2H),7.66 (1H), 8.22 (1H), 8.83 (1H).

Example 2632-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methoxy-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 68 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 261e and 35 mgof 2,2,2-trifluoroethylamine in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.09-1.35 (2H), 1.37-1.75 (2H),2.21-2.41 (1H), 2.69-2.88 (1H), 2.92-3.19 (1H), 3.42-3.69 (1H), 4.13(2H), 4.23 (3H), 4.35 (3H), 7.26 (1H), 7.34-7.45 (2H), 7.46-7.55 (2H),7.61 (1H), 8.59 (1H), 8.88 (1H).

Example 2642-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-ethoxyethyl)-4-methoxy-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 60 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 261e and 31 mgof 2-ethoxyethylamine in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.14 (3H), 1.19-1.35 (2H), 1.37-1.72(2H), 2.23-2.43 (1H), 2.68-2.88 (1H), 2.91-3.15 (1H), 3.41-3.56 (m, 7H),4.20 (3H), 4.34 (3H), 7.25 (1H), 7.33-7.45 (2H), 7.46-7.55 (2H), 7.67(1H), 8.23 (1H), 8.83 (1H).

Example 2652-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methoxy-N-{2-[(trifluoro-methyl)sulphanyl]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 68 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 261e and 51 mgof 2-[(trifluoromethyl)sulphanyl]-ethylamine in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.14-1.35 (2H), 1.36-1.72 (2H),2.18-2.40 (1H), 2.66-2.87 (1H), 2.91-3.11 (1H), 3.21 (2H), 3.42-3.70(3H), 4.22 (3H), 4.34 (3H), 7.24 (1H), 7.32-7.45 (2H), 7.46-7.55 (2H),7.64 (1H), 8.45 (1H), 8.85 (1H).

Example 2664-methoxy-N-(2-methoxyethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 84 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 266b and 89 mgof 4-(trifluoromethoxy)benzoic acid in DMF.

LC-MS: R_(t)=1.16 min, MS (ES+): m/z=435 (M+H)⁺.

The starting material was prepared as follows:

Example 266a Tert-butyl4-({4-methoxy-5-[N-(2-methoxyethyl)carbamoyl]-2H-indazol-2-yl}methyl)piperidin-1-carboxylate

3 g of compound 261a, 1.59 g of 2-methoxyethylamine, 1.87 g ofmolybdenum hexacarbonyl, 204 mg of tri-tert-butylphosphinetetrafluoroborate and 316 mg of palladium(II) acetate were firstsuspended in 100 ml 1,4-dioxan. Then 2.25 g of sodium carbonate and afew drops of water were added, and the mixture stirred for 25 mins at140° C. and 150 watts in the microwave. The reaction mixture wasconcentrated and the residue was purified by column chromatography onsilica gel using a hexane/ethyl acetate/methanol gradient. Yield: 1.3 gof the title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.99-1.22 (2H), 1.29-1.55 (11H),2.03-2.33 (1H), 2.60-2.83 (2H), 3.28-3.31 (3H), 3.43-3.52 (4H),3.82-4.03 (2H), 4.20 (3H), 4.31 (2H), 7.25 (1H), 7.66 (1H), 8.21 (1H),8.82 (1H).

Example 266b4-methoxy-N-(2-methoxyethyl)-2-(4-piperidylmethyl)-2H-indazol-5-carboxamide

Analogously to Example 258b, from 1.3 g of the compound prepared inExample 266a, 1.48 g of the title compound was obtained, which was usedin the subsequent reactions without further purification.

Example 2672-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 20 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 266b and 90 mgof 2-fluoro-4-(trifluoromethyl)benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.05-1.36 (2H), 1.39-1.53 (1H),1.56-1.72 (1H), 2.21-2.40 (1H), 2.75-2.90 (1H), 2.92-3.15 (1H),3.27-3.35 (4H), 3.44-3.53 (4H), 4.20 (3H), 4.27-4.43 (2H), 4.44-4.58(1H), 7.25 (1H), 7.54-7.74 (3H), 7.81 (1H), 8.20 (1H), 8.83 (1H).

Example 2684-methoxy-N-(2-methoxyethyl)-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 39 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 266b and 107 mgof 4-(pentafluoro-λ⁶-sulphanyl)benzoic acid in DMF.

LC-MS: R_(t)=1.18 min, MS (ES+): m/z=577 (M+H)⁺.

Example 2694-methoxy-N-(2-methoxyethyl)-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 25 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 266b and 96 mgof 4-[(trifluoromethyl)sulphanyl]benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm], 1.09-1.37 (2H), 1.38-1.72 (2H),2.23-2.39 (1H), 2.70-2.93 (1H), 2.95-3.16 (1H), 3.30 (3H), 3.40-3.55(5H), 4.20 (3H), 4.35 (d, 3H), 7.25 (1H), 7.46-7.58 (2H), 7.66 (1H),7.78 (2H), 8.20 (1H), 8.82 (1H).

Example 2702-({1-[4-chloro-3-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 27 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 266b and 97 mgof 4-chloro-3-(trifluoromethyl)benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.15-1.37 (2H), 1.38-1.73 (2H),2.14-2.41 (1H), 2.70-2.88 (1H), 2.95-3.18 (1H), 3.30 (3H), 3.39-3.62(5H), 4.20 (3H), 4.35 (3H), 7.25 (1H), 7.59-7.73 (2H), 7.75-7.86 (2H),8.20 (1H), 8.82 (1H).

Example 2712-{[1-(4-chloro-2-fluorobenzoyl)piperidin-4-yl]methyl}-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 17 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 266b and 75 mgof 4-chloro-2-fluorobenzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.08-1.33 (2H), 1.37-1.52 (1H),1.53-1.70 (1H), 2.20-2.42 (1H), 2.72-2.88 (1H), 2.94-3.12 (1H), 3.30(3H), 3.37 (1H), 3.43-3.51 (4H), 4.20 (3H), 4.34 (2H), 4.42-4.55 (1H),7.25 (1H), 7.31-7.48 (2H), 7.55 (1H), 7.66 (1H), 8.20 (1H), 8.83 (1H).

Example 2722-({1-[3-fluoro-4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 12 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 266b and 97 mgof 3-fluoro-4-(trifluoromethoxy)benzoic acid in DMF.

LC-MS: R_(t)=1.18 min, MS (ES+): m/z=553 (M+H)⁺.

Example 2734-methoxy-N-(2-methoxyethyl)-2-({1-[(1-methyl-1H-indol-3-yl)carbonyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 19 mg of the title compound wasobtained from 100 mg of the compound prepared in Example 266b and 76 mgof 1-methyl-1H-indol-3-carboxylic acid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.11-1.40 (2H), 1.54 (2H), 2.18-2.42(1H), 2.93 (2H), 3.30 (3H), 3.40-3.45 (4H), 3.70-3.91 (3H), 4.12-4.48(7H), 7.00-7.34 (3H), 7.48 (1H), 7.66 (3H), 8.22 (1H), 8.84 (1H).

Example 2742-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-ethoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 47 mg of the title compound wasobtained from 110 mg of the compound prepared in Example 274c and 72 mgof 4-chlorobenzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.10-1.33 (2H), 1.44 (5H), 2.20-2.39(1H), 2.68-2.85 (1H), 2.92-3.12 (1H), 3.32 (7H), 3.51-3.62 (1H),4.20-4.59 (5H), 7.26 (1H), 7.33-7.44 (2H), 7.47-7.55 (2H), 7.70 (1H),8.30 (1H), 8.79 (1H).

The starting material was prepared as follows:

Example 274a Tert-butyl4-[(5-bromo-4-ethoxy-2H-indazol-2-yl)methyl]piperidin-1-carboxylate

Analogously to Example 74c, 285 mg of the title compound was obtainedfrom 484 mg of 5-bromo-4-ethoxy-1H-indazole and 1.11 g oftert-butyl-4-[(5-bromo-4-ethoxy-2H-indazol-2-yl)-methyl]piperidin-1-carboxylate.

¹H-NMR (400 MHz, chloroform-d): δ [ppm], 1.13-1.34 (2H), 1.46 (9H), 1.49(3H), 1.56-1.63 (2H), 2.16-2.37 (1H), 2.54-2.80 (2H), 4.02-4.21 (2H),4.26 (2H), 4.33 (2H), 7.28-7.43 (2H), 7.93 (1H).

Example 274b Tert-butyl4-({4-ethoxy-5-[N-(2-methoxyethyl)carbamoyl]-2H-indazol-2-yl}-methyl)piperidin-1-carboxylate

Analogously to Example 266a, 235 mg of the title compound was obtainedfrom 285 mg of the compound prepared in Example 274a and 146 mg of2-methoxyethylamine.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.97-1.22 (2H), 1.29-1.56 (14H),2.06-2.31 (1H), 2.59-2.86 (2H), 3.33 (3H), 3.49 (4H), 3.80-4.02 (2H),4.30 (2H), 4.51 (2H), 7.26 (1H), 7.71 (1H), 8.31 (1H), 8.79 (1H).

Example 274c4-ethoxy-N-(2-methoxyethyl)-2-(4-piperidylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 258b, from 235 mg of the compound prepared inExample 274b, 237 mg of the title compound was obtained, which wasreacted in the next step without further purification.

Example 2754-ethoxy-N-(2-methoxyethyl)-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 30 mg of the title compound wasobtained from 110 mg of the compound prepared in Example 274c and 113 mgof 4-(pentafluoro-2⁶-sulphanyl)benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.10-1.36 (2H), 1.44 (4H), 1.54-1.69(1H), 2.22-2.40 (1H), 2.70-2.87 (1H), 2.93-3.13 (1H), 3.30 (3H), 3.48(5H), 4.34 (2H), 4.41-4.63 (3H), 7.26 (1H), 7.59 (2H), 7.70 (1H), 7.98(2H), 8.30 (1H), 8.79 (1H).

Example 2762-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-ethoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 25 mg of the title compound wasobtained from 50 mg of the compound prepared in Example 276c and 35 mgof 4-chlorobenzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.44 (3H), 3.21-3.29 (1H), 3.31(3H), 3.49 (4H), 3.96 (1H), 4.06-4.30 (2H), 4.34-4.59 (3H), 4.69 (2H),7.25 (1H), 7.51 (2H), 7.62 (2H), 7.71 (1H), 8.30 (1H), 8.86 (1H).

The starting material was prepared as follows:

Example 276a Tert-butyl3-[(5-bromo-4-ethoxy-2H-indazol-2-yl)methyl]azetidin-1-carboxylate

Analogously to Example 74c, 204 mg of the title compound was obtainedfrom 500 mg of 5-bromo-4-ethoxy-1H-indazole and 1.06 g oftert-butyl-3-[(tosyloxy)methyl]azetidin-1-carboxylate.

¹H-NMR (600 MHz, chloroform-d): δ [ppm], 1.44 (9H), 1.49 (3H), 3.14-3.30(1H), 3.72-3.83 (2H), 4.07 (2H), 4.33 (2H), 4.59 (2H), 7.29 (1H), 7.37(1H), 7.98 (1H).

Example 276b Tert-butyl3-({4-ethoxy-5-[N-(2-methoxyethyl)carbamoyl]-2H-indazol-2-yl}-methyl)azetidin-1-carboxylate

Analogously to Example 266a, from 191 mg of the compound prepared inExample 276a and 105 mg of 2-methoxyethylamine, 121 mg of the titlecompound was obtained, which was reacted in the next step withoutfurther purification.

Example 276c2-(azetidin-3-ylmethyl)-4-ethoxy-N-(2-methoxyethyl)-2H-indazol-5-carboxamide

Analogously to Example 258b, from 121 mg of the compound prepared inExample 276b, 93 mg of the title compound was obtained, which wasreacted in the next step without further purification.

Example 2774-ethoxy-N-(2-methoxyethyl)-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]-azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 35 mg of the title compound wasobtained from 50 mg of 276c and 56 mg of 4-(pentafluoro-λ2⁶-sulphanyl)benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.37-1.50 (3H), 3.26 (1H), 3.31(3H), 3.43-3.57 (4H), 3.92-4.05 (1H), 4.10-4.31 (2H), 4.38-4.57 (3H),4.70 (2H), 7.25 (1H), 7.66-7.87 (3H), 7.98 (2H), 8.30 (1H), 8.86 (1H).

Example 2782-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-6-methyl-N-(2-morpholinoethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 23 mg of the title compound wasobtained from 100 mg of 278b and 66 mg of 4-chlorobenzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 2.42 (s, 3H), 3.09-3.27 (m, 3H),3.29-3.33 (2H), 3.49-3.73 (m, 6H), 3.84-3.96 (m, 1H), 3.97-4.15 (m, 3H),4.16-4.27 (m, 1H), 4.31-4.45 (m, 1H), 4.62-4.80 (m, 2H), 7.36-7.47 (1H),7.48-7.57 (2H), 7.58-7.70 (2H), 7.77-7.89 (1H), 8.41-8.58 (2H).

The starting material was prepared as follows:

Example 278a Tert-butyl3-({6-methyl-5-[N-(2-morpholinoethyl)carbamoyl]-2H-indazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1b, Version B, 418 mg of the title compound wasobtained from 410 mg of 178c and 232 mg of 2-morpholinoethylamine inDMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.36 (9H), 2.39 (3H), 2.44 (4H),2.95-3.17 (1H), 3.24-3.43 (4H), 3.58 (4H), 3.64-3.79 (2H), 3.88 (2H),4.62 (2H), 7.39 (1H), 7.68 (1H), 8.04-8.22 (1H), 8.45 (1H).

Example 278b2-(azetidin-3-ylmethyl)-6-methyl-N-(2-morpholinoethyl)-2H-indazole-5-carboxamide

Analogously to Example 258b, from 400 mg of the compound prepared inExample 278a, 372 mg of the title compound was obtained, which wasreacted in the next step without further purification.

Example 2796-methyl-N-(2-morpholinoethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 44 mg of the title compound wasobtained from 100 mg of 278b and 86 mg of 4-(trifluoromethoxy)benzoicacid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 2.42 (3H), 3.07-3.27 (5H), 3.48-3.74(6H), 3.85-4.17 (4H), 4.18-4.29 (1H), 4.33-4.48 (1H), 4.61-4.82 (2H),7.30-7.54 (3H), 7.68-7.78 (2H), 7.79-7.88 (1H), 8.43-8.60 (2H).

Example 2806-methyl-N-(2-morpholinoethyl)-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]-azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 37 mg of the title compound wasobtained from 100 mg of 278b and 104 mg of4-(pentafluoro-λ⁶-sulphanyl)benzoic acid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 2.42 (3H), 3.06-3.27 (5H), 3.47-3.75(6H), 3.87-4.08 (3H), 4.09-4.29 (2H), 4.33-4.49 (1H), 4.61-4.80 (2H),7.34-7.52 (1H), 7.71-7.88 (3H), 7.92-8.07 (2H), 8.39-8.59 (2H).

Example 281N-(2-methoxyethyl)-6-methyl-2-({1-[(1-methyl-1H-indol-3-yl)carbonyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 4.2 mg of the title compound wasobtained from 150 mg of 205c and 119 mg of1-methyl-1H-indol-3-carboxylic acid in DMF.

LC-MS: R_(t)=1.01 min, MS (ES+): m/z=489 (M+H)⁺.

Example 282N-(2-methoxyethyl)-4-methyl-2-({1-[(1-methyl-1H-indol-3-yl)carbonyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 35 mg of the title compound wasobtained from 175 mg of 117e and 122 mg of1-methyl-1H-indol-3-carboxylic acid in DMF.

LC-MS: R_(t)=0.95 min, MS (ES+): m/z=460 (M+H)⁺.

Example 2832-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 267 mg of the title compound wasobtained from 250 mg of 71a and 246 mg of 4-(4-fluorophenoxy)benzoicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.16-1.32 (2H), 1.35-1.69 (2H),2.20-2.39 (1H), 2.54 (3H), 2.70-3.15 (2H), 3.50-3.83 (1H), 4.07 (2H),4.36 (3H), 6.91-7.05 (2H), 7.08-7.31 (5H), 7.34-7.42 (2H), 7.46 (1H),8.56 (1H), 8.83 (1H).

Example 2842-({1-[4-(4-chlorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 55 mg of the title compound wasobtained from 100 mg of 71a and 105 mg of 4-(4-chlorophenoxy)benzoicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.34-1.72 (2H), 2.21-2.41(1H), 2.54 (3H), 2.67-3.20 (2H), 3.51-3.83 (1H), 4.07 (2H), 4.36 (3H),6.92-7.15 (4H), 7.20 (1H), 7.35-7.53 (5H), 8.56 (1H), 8.84 (1H).

Example 2854-methyl-2-({1-[4-(4-methylphenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 60 mg of the title compound wasobtained from 100 mg of 71a and 97 mg of 4-(4-methylphenoxy)benzoic acidin DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.36-1.71 (2H), 2.30(4H), 2.54 (3H), 2.64-3.17 (2H), 3.49-3.82 (1H), 4.07 (2H), 4.36 (3H),6.85-7.04 (4H), 7.21 (3H), 7.29-7.41 (2H), 7.46 (1H), 8.56 (1H), 8.84(s1H).

Example 2862-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 39 mg of the title compound wasobtained from 100 mg of 71a and 92 mg of 4-(4-fluorophenyl)benzoic acidin DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.14-1.36 (2H), 1.36-1.73 (2H),2.18-2.41 (1H), 2.54 (3H), 2.70-3.16 (2H), 3.51-3.82 (1H), 4.07 (2H),4.38 (3H), 7.21 (1H), 7.31 (2H), 7.40-7.53 (3H), 7.64-7.85 (4H), 8.56(1H), 8.81 (1H).

Example 2874-methyl-2-{[1-(4-morpholinobenzoyl)piperidin-4-yl]methyl}-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 45 mg of the title compound wasobtained from 100 mg of 71a and 88 mg of 4-morpholinobenzoic acid inDMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.24 (2H), 1.40-1.60 (2H), 2.20-2.40(1H), 2.54 (3H), 2.73-3.01 (2H), 3.38 (4H), 3.64-3.81 (5H), 4.07 (3H),4.36 (2H), 6.94 (2H), 7.16-7.30 (3H), 7.46 (1H), 8.55 (1H), 8.81 (1H).

Example 2884-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 67 mg of the title compound wasobtained from 100 mg of 71a and 94 mg of4-[(trifluoromethyl)sulphanyl]benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.12-1.35 (2H), 1.35-1.70 (2H),2.21-2.40 (1H), 2.54 (3H), 2.70-2.88 (1H), 2.94-3.12 (1H), 3.38-3.61(1H), 4.07 (2H), 4.36 (3H), 7.21 (1H), 7.37-7.60 (3H), 7.78 (2H), 8.55(1H), 8.81 (1H).

Example 2894-methyl-2-({1-[(1-methyl-1H-indol-3-yl)carbonyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 43 mg of the title compound wasobtained from 100 mg of 71a and 74 mg of 1-methyl-1H-indol-3-carboxylicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.27 (2H), 1.52 (2H), 2.20-2.40(1H), 2.54 (3H), 2.92 (2H), 3.82 (3H), 4.07 (2H), 4.27 (2H), 4.38 (2H),6.92-7.33 (3H), 7.47 (2H), 7.61-7.76 (2H), 8.56 (1H), 8.81 (1H).

Example 2904-methyl-2-({1-[(1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 51 mg of the title compound wasobtained from 100 mg of 71a and 74 mg of 1-methyl-1H-indol-2-carboxylicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.17-1.41 (2H), 1.43-1.73 (2H),2.19-2.43 (1H), 2.54 (3H), 2.74-3.23 (2H), 3.73 (3H), 4.07 (3H), 4.39(3H), 6.60 (s, 1H), 7.03-7.14 (1H), 7.16-7.30 (2H), 7.48 (2H), 7.59(1H), 8.57 (1H), 8.81 (1H).

Example 2914-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 156 mg of the title compound wasobtained from 150 mg of 71a and 179 mg of4-[4-(trifluoromethyl)phenoxy]benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.36-1.68 (2H), 2.20-2.43(1H), 2.54 (3H), 2.68-3.17 (2H), 3.50-3.79 (1H), 4.07 (2H), 4.37 (3H),7.09-7.28 (5H), 7.35-7.51 (3H), 7.76 (2H), 8.56 (1H), 8.83 (1H).

Example 2922-({1-[(5-fluoro-1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 28 mg of the title compound wasobtained from 100 mg of 71a and 82 mg of5-fluoro-1-methyl-1H-indol-2-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.18-1.38 (2H), 1.39-1.72 (2H),2.25-2.42 (1H), 2.54 (3H), 2.74-3.25 (2H), 3.73 (3H), 4.07 (3H), 4.38(3H), 6.58 (1H), 7.09 (1H), 7.21 (1H), 7.36 (1H), 7.47 (2H), 8.57 (1H),8.83 (1H).

Example 2932-({1-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 37 mg of the title compound wasobtained from 100 mg of 71a and 87 mg of5-methoxy-1-methyl-1H-indol-2-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.30 (2H), 1.41-1.71 (2H), 2.26-2.43(1H), 2.54 (3H), 2.71-3.22 (2H), 3.69 (3H), 3.75 (3H), 4.07 (3H), 4.39(3H), 6.51 (1H), 6.88 (1H), 7.07 (1H), 7.21 (1H), 7.34-7.54 (2H), 8.57(1H), 8.83 (1H).

Example 2942-({1-[(5-chloro-1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 43 mg of the title compound wasobtained from 100 mg of 71a and 89 mg of5-chloro-1-methyl-1H-indol-2-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.29 (2H), 1.38-1.72 (2H), 2.26-2.43(1H), 2.54 (3H), 2.71-3.21 (2H), 3.73 (3H), 3.84-4.18 (3H), 4.38 (3H),6.59 (1H), 7.15-7.28 (2H), 7.47 (1H), 7.55 (1H), 7.65 (1H), 8.57 (1H),8.83 (1H).

Example 2952-({1-[(6-methoxy-1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 36 mg of the title compound wasobtained from 100 mg of 71a and 87 mg of6-methoxy-1-methyl-1H-indol-2-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.28 (2H), 1.52 (2H), 2.25-2.43(1H), 2.54 (3H), 2.78-3.16 (2H), 3.70 (3H), 3.82 (3H), 3.97-4.63 (6H),6.54 (1H), 6.73 (1H), 7.01 (1H), 7.21 (1H), 7.39-7.53 (2H), 8.57 (1H),8.83 (t1H).

Example 2962-{[1-(1H-Indol-2-ylcarbonyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 43 mg of the title compound wasobtained from 100 mg of 71a and 68 mg of indol-2-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.16-1.40 (2H), 1.58 (2H), 2.27-2.44(1H), 2.55 (3H), 2.77-3.24 (2H), 4.07 (2H), 4.30-4.59 (4H), 6.74 (1H),6.95-7.08 (1H), 7.10-7.26 (2H), 7.40 (1H), 7.48 (1H), 7.59 (1H), 8.58(1H), 8.84 (1H), 11.54 (1H).

Example 2974-methyl-2-({1-[(1-methyl-1H-benzimidazol-2-yl)carbonyl]piperidin-4-yl}-methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 26 mg of the title compound wasobtained from 100 mg of 71a and 75 mg of1-methyl-1H-benzimidazol-2-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.17-1.42 (2H), 1.46 (1H), 1.57-1.75(1H), 2.27-2.44 (1H), 2.54 (3H), 2.87 (1H), 3.11 (1H), 3.83 (3H), 4.07(3H), 4.40 (2H), 4.48-4.62 (1H), 7.13-7.41 (3H), 7.47 (1H), 7.58-7.76(2H), 8.58 (1H), 8.83 (1H).

Example 2984-methyl-2-({1-[(2-phenylthiazol-5-yl)carbonyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 53 mg of the title compound wasobtained from 100 mg of 71a and 87 mg of 2-phenylthiazol-5-carboxylicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.18-1.41 (2H), 1.56 (2H), 2.27-2.44(1H), 2.54 (3H), 2.73-3.29 (2H), 3.93-4.53 (6H), 7.21 (1H), 7.42-7.61(4H), 7.93-8.03 (2H), 8.14 (1H), 8.57 (1H), 8.83 (1H).

Example 2992-{[1-(benzoxazol-2-ylcarbonyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 20 mg of the title compound wasobtained from 100 mg of 71a and 69 mg of benzoxazol-2-carboxylic acid inDMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.19-1.44 (2H), 1.48-1.72 (2H),2.29-2.46 (1H), 2.54 (3H), 2.82-3.01 (1H), 3.12-3.31 (1H), 4.07 (2H),4.40 (4H), 7.21 (1H), 7.42-7.61 (3H), 7.78-7.95 (2H), 8.58 (1H), 8.83(1H).

Example 3004-methyl-2-({1-[(2-phenyloxazol-5-yl)carbonyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 20 mg of the title compound wasobtained from 100 mg of 71a and 80 mg of 2-phenyloxazol-5-carboxylicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.15-1.43 (2H), 1.59 (2H), 2.31-2.45(1H), 2.55 (3H), 2.70-3.35 (2H), 4.07 (2H), 4.39 (4H), 7.21 (1H), 7.48(1H), 7.53-7.67 (3H), 7.80 (1H), 7.94-8.07 (2H), 8.58 (1H), 8.83 (1H).

Example 3014-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]-oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 23 mg of the title compound wasobtained from 75 mg of 71a and 90 mg of4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.13-1.35 (2H), 1.37-1.72 (2H),2.19-2.42 (1H), 2.54 (3H), 2.69-3.17 (2H), 3.55-3.82 (1H), 3.91-4.18(2H), 4.26-4.60 (3H), 7.28 (4H), 7.38-7.56 (3H), 8.16-8.33 (1H),8.49-8.63 (2H), 8.75-8.91 (1H).

Example 3022-{[1-(benzothiazol-2-ylcarbonyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 35 mg of the title compound wasobtained from 75 mg of 71a and 57 mg of benzothiazol-2-carboxylic acidin DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.36 (2H), 1.59 (2H), 2.31-2.46(1H), 2.55 (3H), 2.91 (1H), 3.26 (1H), 4.07 (2H), 4.31-4.61 (3H),4.95-5.23 (1H), 7.21 (1H), 7.41-7.69 (3H), 8.05-8.28 (2H), 8.58 (1H),8.83 (1H).

Example 3034-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]-oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 42 mg of the title compound wasobtained from 75 mg of 71a and 90 mg of the carboxylic acid prepared inExample 303b) in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.16-1.33 (2H), 1.34-1.67 (2H),2.21-2.39 (1H), 2.54 (3H), 2.68-3.16 (2H), 3.52-3.76 (1H), 3.95-4.16(2H), 4.28-4.61 (3H), 7.13-7.31 (3H), 7.46 (3H), 7.59-7.71 (1H), 7.92(1H), 8.52-8.65 (2H), 8.84 (1H).

The starting material was prepared as follows:

Example 303a 4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzonitrile

2.5 g of 5-bromo-2-(trifluoromethyl)pyridine, 5.8 g of4-hydroxybenzonitrile, 10.8 g of caesium carbonate and 1.87 g ofmolybdenum hexacarbonyl in 100 ml 1,4-dioxan were heated under refluxuntil complete conversion. The reaction mixture was diluted with water,extracted several times with ethyl acetate, and the combined organicphases washed with saturated sodium chloride solution, dried over sodiumsulphate and concentrated. The residue was purified by columnchromatography on silica gel using a hexane/ethyl acetate gradient.Yield: 1.35 g of the title compound.

¹H-NMR (300 MHz, DMSO-d6): δ [ppm], 7.35 (2H), 7.75-7.84 (1H), 7.89-8.03(3H), 8.66 (1H).

Example 303b 4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid

1.33 g of the compound prepared in Example 303a in 64 ml ethanol wastreated with 32 ml of 40% potassium hydroxide solution and heated underreflux until complete conversion. The reaction mixture was diluted withwater and extracted with ethyl acetate. The organic phase was washedwith saturated sodium chloride solution, dried over sodium sulphate andconcentrated. Yield: 1.32 g of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 7.19-7.33 (2H), 7.68-7.81 (1H),7.90-8.08 (3H), 8.64 (1H), 12.71-13.28 (1H).

Example 3044-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]-oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 48 mg of the title compound wasobtained from 75 mg of 71a and 90 mg of4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.15-1.34 (2H), 1.35-1.71 (2H),2.23-2.41 (1H), 2.54 (3H), 2.67-3.17 (2H), 3.51-3.77 (1H), 3.97-4.18(2H), 4.22-4.65 (3H), 7.13-7.31 (3H), 7.37 (1H), 7.41-7.53 (3H), 7.67(1H), 8.07-8.20 (1H), 8.57 (1H), 8.75-8.92 (1H).

Example 3054-methyl-2-({1-[(3-phenyl-1,2,4-oxadiazol-5-yl)carbonyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 40 mg of the title compound wasobtained from 90 mg of 71a and 73 mg of3-phenyl-1,2,4-oxadiazol-5-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.18-1.43 (2H), 1.48-1.72 (2H),2.33-2.47 (1H), 2.54 (3H), 2.95 (1H), 3.24 (1H), 3.94-4.17 (3H),4.33-4.53 (3H), 7.21 (1H), 7.47 (1H), 7.55-7.70 (3H), 7.96-8.12 (2H),8.57 (1H), 8.83 (1H).

Example 3062-({1-[4-(4-cyanophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 59 mg of the title compound wasobtained from 110 mg of 71a and 101 mg of 4-(4-cyanophenoxy)benzoic acidin DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.17-1.34 (2H), 1.35-1.70 (2H),2.18-2.41 (1H), 2.54 (3H), 2.70-3.18 (2H), 3.54-3.79 (1H), 4.07 (2H),4.37 (3H), 7.10-7.28 (5H), 7.41-7.52 (3H), 7.79-7.94 (2H), 8.56 (s1H),8.81 (s1H).

Example 3072-({1-[4-(3-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 40 mg of the title compound wasobtained from 100 mg of 71a and 89 mg of 4-(3-fluorophenoxy)benzoic acidin DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.14-1.34 (2H), 1.36-1.70 (2H),2.22-2.44 (1H), 2.54 (3H), 2.70-3.13 (2H), 3.52-3.86 (1H), 4.07 (2H),4.37 (3H), 6.79-7.12 (5H), 7.21 (1H), 7.35-7.52 (4H), 8.55 (1H), 8.81(1H).

Example 3084-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[3-(trifluoromethyl)phenoxy]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 47 mg of the title compound wasobtained from 100 mg of 71a and 119 mg of4-[3-(trifluoromethyl)phenoxy]benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.16-1.34 (2H), 1.37-1.66 (2H),2.22-2.38 (1H), 2.54 (3H), 2.69-3.14 (2H), 3.50-3.83 (1H), 4.07 (2H),4.37 (3H), 7.10 (2H), 7.21 (1H), 7.36 (1H), 7.39-7.50 (4H), 7.54 (1H),7.61-7.75 (1H), 8.55 (1H), 8.81 (1H).

Example 3094-methyl-2-({1-[(5-phenyloxazol-2-yl)carbonyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 10 mg of the title compound wasobtained from 100 mg of 71a and 73 mg of 5-phenyloxazol-2-carboxylicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.24 (2H), 1.58 (2H), 2.29-2.45(1H), 2.55 (3H), 2.86 (1H), 3.21 (1H), 4.07 (2H), 4.31-4.52 (3H), 4.62(1H), 7.21 (1H), 7.39-7.57 (4H), 7.74-7.83 (2H), 7.88 (1H), 8.57 (1H),8.81 (1H).

Example 3102-[(1-{4-[(5-cyanopyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 47 mg of the title compound wasobtained from 100 mg of 71a and 119 mg of4-[3-(trifluoromethyl)phenoxy]benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.16-1.34 (2H), 1.37-1.66 (2H),2.22-2.38 (1H), 2.54 (3H), 2.69-3.14 (2H), 3.50-3.83 (1H), 4.07 (2H),4.37 (3H), 7.10 (2H), 7.21 (1H), 7.36 (1H), 7.39-7.50 (4H), 7.54 (1H),7.61-7.75 (1H), 8.55 (1H), 8.81 (1H).

Example 3112-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 72 mg of the title compound wasobtained from 100 mg of 71a and 96 mg of4-[(5-chloropyridin-2-yl)oxy]benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.17-1.34 (2H), 1.36-1.73 (2H),2.22-2.41 (1H), 2.54 (3H), 2.69-3.18 (2H), 3.47-3.88 (1H), 4.07 (2H),4.37 (3H), 7.06-7.28 (4H), 7.34-7.52 (3H), 7.99 (1H), 8.22 (1H), 8.56(1H), 8.81 (1H).

Example 3124-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[5-(trifluoromethyl)pyridin-2-yl]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 83 mg of the title compound wasobtained from 100 mg of 71a and 103 mg of4-[5-(trifluoromethyl)pyridin-2-yl]benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.28 (2H), 1.36-1.73 (2H), 2.33(1H), 2.54 (3H), 2.70-3.18 (2H), 3.47-3.76 (1H), 3.96-4.16 (2H), 4.38(3H), 7.21 (1H), 7.41-7.60 (3H), 8.17-8.40 (4H), 8.56 (1H), 8.81 (1H),9.07 (1H).

Example 3132-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 87 mg of the title compound wasobtained from 100 mg of 71a and 96 mg of 4-(2,4-difluorophenoxy)benzoicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.34-1.72 (2H), 2.18-2.42(1H), 2.52-2.58 (3H), 2.69-3.20 (2H), 3.43-3.84 (1H), 4.07 (2H), 4.36(3H), 6.92-7.06 (2H), 7.09-7.25 (2H), 7.28-7.42 (3H), 7.43-7.61 (2H),8.55 (1H), 8.81 (1H).

Example 3142-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 48 mg of the title compound wasobtained from 100 mg of 71a and 96 mg of 4-(3,4-difluorophenoxy)benzoicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.24 (2H), 1.36-1.72 (2H), 2.19-2.42(1H), 2.54 (3H), 2.70-3.17 (2H), 3.44-3.86 (1H), 3.99-4.17 (2H), 4.36(3H), 6.86-6.97 (1H), 7.01-7.11 (2H), 7.21 (1H), 7.29 (1H), 7.35-7.55(4H), 8.55 (1H), 8.81 (1H).

Example 3154-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{[4′-(trifluoromethyl)biphenyl-4-yl]-carbonyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 32 mg of the title compound wasobtained from 100 mg of 71a and 102 mg of4′-(trifluoromethyl)biphenyl-4-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.27 (2H), 1.37-1.71 (2H), 2.24-2.39(1H), 2.53 (3H), 2.70-3.18 (2H), 3.43-3.51 (2H), 3.54-3.86 (1H), 4.37(3H), 7.18 (1H), 7.38-7.57 (3H), 7.72-7.88 (4H), 7.89-7.98 (2H), 8.13(1H), 8.51 (1H).

Example 3162-{[1-(4-bromobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 6.96 g of the title compound wasobtained from 5.61 g 71a and 2.89 g of 4-bromobenzoic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.17-1.32 (2H), 1.34-1.74 (2H),2.19-2.41 (1H), 2.54 (3H), 2.88-3.22 (2H), 3.42-3.74 (1H), 3.94-4.18(2H), 4.36 (3H), 7.20 (1H), 7.32 (2H), 7.46 (1H), 7.64 (2H), 8.55 (1H),8.83 (1H).

Example 3172-({1-[4-(5-chloropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

80 mg of the aryl bromide prepared in Example 316 together with 32 mg of(5-chloropyridin-2-yl)boronic acid was first placed in 1 mltetrahydrofuran, treated with 17.3 mg of1,1′-bis(diphenylphosphino)ferrocenodichloropalladium(II) and 0.17 ml of1M potassium carbonate solution and heated in the microwave for 10minutes at 120° C. (100 watts). After fresh addition of 11 mg of(5-chloropyridin-2-yl)boronic acid and 17.3 mg of the palladium(II)catalyst, the reaction mixture was again heated in the microwave for 10minutes at 120° C. (100 watts) until complete conversion. The reactionmixture was concentrated. After HPLC purification, this yielded 15 mg ofthe title compound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.18-1.36 (2H), 1.37-1.75 (2H),2.28-2.38 (1H), 2.54 (3H), 2.73-3.18 (2H), 3.49-3.74 (1H), 3.95-4.16(2H), 4.28-4.62 (3H), 7.22 (1H), 7.33-7.65 (5H), 7.98-8.22 (3H), 8.56(1H), 8.77-8.91 (1H).

Example 3182-({1-[(4′-methoxy-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 50 mg of the title compound was obtainedfrom 125 mg of 316 and 53 mg of (4-methoxy-2-methyl-phenyl)boronic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.16-1.36 (2H), 1.37-1.74 (2H), 2.23(3H), 2.29-2.38 (1H), 2.54 (3H), 2.72-3.12 (2H), 3.77 (4H), 3.97-4.17(2H), 4.38 (3H), 6.75-6.94 (2H), 7.07-7.26 (2H), 7.29-7.56 (5H), 8.56(1H), 8.81 (1H).

Example 3194-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 37 mg of the title compound was obtainedfrom 125 mg of 316 and 44 mg of (6-methylpyridin-3-yl)boronic acid underreflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.15-1.35 (2H), 1.37-1.71 (2H),2.20-2.40 (1H), 2.52 (3H), 2.54 (3H), 2.74-3.15 (2H), 3.52-3.82 (1H),4.07 (2H), 4.38 (3H), 7.20 (1H), 7.37 (1H), 7.47 (3H), 7.77 (2H), 8.01(1H), 8.57 (1H), 8.72-8.92 (2H).

Example 3202-({1-[(4′-fluoro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 60 mg of the title compound was obtainedfrom 125 mg of 316 and 75 g of (4-fluoro-2-methoxyphenyl)boronic acidunder reflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.16-1.37 (2H), 1.38-1.75 (2H),2.25-2.37 (1H), 2.54 (3H), 2.72-3.17 (2H), 3.79 (4H), 4.07 (2H), 4.38(3H), 6.87 (1H), 7.04 (1H), 7.21 (1H), 7.27-7.58 (6H), 8.56 (1H), 8.81(1H).

Example 3214-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 317, 45 mg of the title compound was obtainedfrom 125 mg of 316 and 84 mg of [6-(trifluoromethyl)pyridin-3-yl]boronicacid under reflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.15-1.37 (2H), 1.37-1.71 (2H),2.22-2.41 (1H), 2.54 (3H), 2.73-3.20 (2H), 3.45-3.74 (1H), 3.93-4.17(2H), 4.29-4.62 (3H), 7.21 (1H), 7.39-7.62 (4H), 7.89 (2H), 8.01 (1H),8.57 (1H), 8.73-8.92 (1H), 9.13 (1H).

Example 3222-({1-[4-(6-methoxypyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 54 mg of the title compound was obtainedfrom 125 mg of 316 and 68 mg of (6-methoxypyridin-3-yl)boronic acidunder reflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.13-1.35 (2H), 1.36-1.71 (2H),2.20-2.40 (1H), 2.54 (3H), 2.73-3.16 (2H), 3.51-3.77 (1H), 3.90 (3H),3.96-4.19 (2H), 4.37 (3H), 6.93 (1H), 7.20 (1H), 7.39-7.52 (3H), 7.73(2H), 8.05 (1H), 8.47-8.63 (2H), 8.83 (1H).

Example 3232-({1-[4-(6-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 55 mg of the title compound was obtainedfrom 125 mg of 316 and 49 mg of (6-methoxypyridin-2-yl)boronic acidunder reflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.16-1.36 (2H), 1.37-1.69 (2H),2.20-2.41 (1H), 2.54 (3H), 2.74-3.16 (2H), 3.47-3.81 (1H), 3.96 (3H),4.06 (2H), 4.38 (3H), 6.81 (1H), 7.21 (1H), 7.47 (3H), 7.60 (1H),7.74-7.90 (1H), 8.15 (2H), 8.56 (1H), 8.81 (1H).

Example 3244-methyl-2-({1-[4-(5-methylpyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 9 mg of the title compound was obtained from125 mg of 316 and 44 mg of (5-methylpyridin-2-yl)boronic acid underreflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.16-1.36 (2H), 1.37-1.71 (2H),2.24-2.30 (1H), 2.34 (3H), 2.54 (3H), 2.74-3.16 (2H), 3.52-3.79 (1H),3.93-4.17 (2H), 4.38 (3H), 7.20 (1H), 7.37-7.54 (3H), 7.66-7.78 (1H),7.89 (1H), 8.11 (2H), 8.45-8.61 (2H), 8.74-8.88 (1H).

Example 3252-({1-[4-(5-fluoropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 35 mg of the title compound was obtainedfrom 125 mg of 316 and 45 mg of (5-fluoropyridin-2-yl)boronic acid underreflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.17-1.34 (2H), 1.35-1.69 (2H),2.22-2.41 (1H), 2.54 (3H), 2.69-3.19 (2H), 3.51-3.78 (1H), 4.07 (2H),4.38 (3H), 7.20 (1H), 7.40-7.53 (3H), 7.85 (1H), 8.04-8.17 (3H), 8.57(1H), 8.68 (1H), 8.83 (1H).

Example 3262-({1-[4-(5-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 94 mg of the title compound was obtainedfrom 125 mg of 316 and 49 mg of (5-methoxypyridin-2-yl)boronic acidunder reflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.19-1.36 (2H), 1.37-1.69 (2H),2.28-2.40 (1H), 2.54 (3H), 2.73-3.19 (2H), 3.48-3.79 (1H), 3.88 (3H),4.07 (2H), 4.38 (3H), 7.20 (1H), 7.38-7.55 (4H), 7.96 (1H), 8.07 (2H),8.39 (1H), 8.57 (1H), 8.82 (1H).

Example 3274-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 46 mg of the title compound was obtainedfrom 125 mg of 316 and 102 mg of (2-methylpyrimidin-5-yl)boronic acidpinacol ester under reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.16-1.35 (2H), 1.35-1.67 (2H),2.21-2.42 (1H), 2.54 (3H), 2.67 (3H), 2.71-2.89 (1H), 2.93-3.20 (1H),3.50-3.73 (1H), 4.07 (2H), 4.37 (3H), 7.20 (1H), 7.40-7.57 (3H), 7.85(2H), 8.57 (1H), 8.84 (1H), 9.05 (2H).

Example 3284-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 317, 34 mg of the title compound was obtainedfrom 125 mg of 316 and 89 mg of[2-(trifluoromethyl)pyrimidin-5-yl]boronic acid under reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.21-1.35 (2H), 1.36-1.71 (2H),2.23-2.41 (1H), 2.54 (3H), 2.71-2.89 (1H), 2.94-3.17 (1H), 3.48-3.72(1H), 4.05 (2H), 4.28-4.61 (3H), 7.21 (1H), 7.47 (1H), 7.57 (2H), 7.98(2H), 8.57 (1H), 8.84 (1H), 9.44 (2H).

Example 3294-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 317, 70 mg of the title compound was obtainedfrom 125 mg of 316 and 121 mg of[6-(trifluoromethyl)pyridin-2-yl]boronic acid pinacol ester underreflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.19-1.36 (2H), 1.37-1.72 (2H),2.23-2.39 (1H), 2.54 (3H), 2.68-2.90 (1H), 2.92-3.16 (1H), 3.50-3.73(1H), 4.06 (2H), 4.38 (3H), 7.20 (1H), 7.41-7.60 (3H), 7.89 (1H),8.11-8.27 (3H), 8.33 (1H), 8.56 (1H), 8.81 (1H).

Example 3302-({1-[4-(4-cyanophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 151 mg of the title compound wasobtained from 213 mg of 71a and 153 mg of 4-(4-cyanophenoxy)benzoic acidin DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.22 (2H), 1.31-1.66 (2H), 2.15-2.36(1H), 2.49 (3H), 2.70-3.12 (2H), 3.24 (3H), 3.36 (2H), 3.39-3.46 (2H),3.50-3.79 (1H), 4.32 (3H), 7.00-7.23 (5H), 7.30-7.49 (3H), 7.75-7.91(2H), 8.12 (1H), 8.48 (1H).

Example 331N-(2-methoxyethyl)-4-methyl-2-({1-[(1-methyl-1H-indol-3-yl)carbonyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 26 mg of the title compound wasobtained from 38 mg of 71a and 36 mg of 1-methyl-1H-indol-3-carboxylicacid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.43-1.64 (2H), 2.20-2.39(1H), 2.53 (3H), 2.80-3.03 (2H), 3.28 (3H), 3.37-3.50 (4H), 3.81 (3H),4.37 (4H), 7.18 (3H), 7.36-7.53 (2H), 7.67 (2H), 8.04-8.25 (1H), 8.52(1H).

Example 3322-{[1-(4-bromo-3-methylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 498 mg of the title compound wasobtained from 807 mg of 71a and 788 mg of 4-bromo-3-methylbenzoic acidin DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.20-1.32 (2H), 1.33-1.67 (2H),2.24-2.33 (1H), 2.36 (3H), 2.52 (3H), 2.73 (1H), 2.91-3.13 (1H), 3.28(3H), 3.35-3.63 (5H), 4.34 (3H), 7.03-7.23 (2H), 7.30-7.49 (2H), 7.63(1H), 8.15 (1H), 8.51 (1H).

Example 3332-{[1-(4-tert-butylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 50 mg of the title compound wasobtained from 100 mg of 71a and 81 mg of 4-tert-butylbenzoic acid inDMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.20-1.33 (11H), 1.33-1.67 (2H),2.21-2.37 (1H), 2.52 (3H), 2.68-3.10 (2H), 3.28 (3H), 3.36-3.43 (2H),3.45 (2H), 3.52-3.74 (1H), 4.35 (3H), 7.18 (1H), 7.25-7.35 (2H),7.36-7.52 (3H), 8.15 (1H), 8.50 (1H).

Example 3342-({1-[4-(1-hydroxy-1-methylethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 28 mg of the title compound wasobtained from 100 mg of 71a and 82 mg of4-(1-hydroxy-1-methylethyl)benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.24 (2H), 1.42 (8H), 2.20-2.40(1H), 2.52 (3H), 2.64-3.11 (2H), 3.28 (3H), 3.34-3.43 (2H), 3.43-3.51(2H), 3.53-3.71 (1H), 4.35 (3H), 4.76-5.43 (1H), 7.18 (1H), 7.28 (2H),7.42 (1H), 7.46-7.56 (2H), 8.15 (1H), 8.51 (1H).

Example 3352-{[1-(4-cyclohexylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 75 mg of the title compound wasobtained from 100 mg of 71a and 93 mg of 4-cyclohexylbenzoic acid inDMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.10-1.63 (9H), 1.64-1.89 (5H),2.17-2.40 (1H), 2.52 (3H), 2.69-3.08 (2H), 3.28 (3H), 3.38-3.43 (2H),3.43-3.49 (2H), 3.53-3.73 (1H), 4.35 (3H), 7.18 (1H), 7.27 (4H), 7.42(1H), 8.15 (1H), 8.50 (1H).

Example 336N-(2-methoxyethyl)-2-{[1-(6-methoxy-2-naphthoyl)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 23 mg of the title compound wasobtained from 100 mg of 71a) and 92 mg of6-methoxy-naphthalen-2-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.37-1.72 (2H), 2.23-2.39(1H), 2.52 (3H), 2.72-3.12 (2H), 3.28 (3H), 3.36-3.42 (2H), 3.43-3.49(2H), 3.59-3.81 (1H), 3.89 (3H), 4.36 (3H), 7.09-7.27 (2H), 7.33-7.49(3H), 7.79-7.95 (3H), 8.15 (1H), 8.51 (1H).

Example 337N-(2-methoxyethyl)-4-methyl-2-({1-[(2-phenylthiazol-5-yl)carbonyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 36 mg of the title compound wasobtained from 100 mg of 71a and 93 mg of 2-phenylthiazol-5-carboxylicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.55 (2H), 2.19-2.45(1H), 2.52-2.56 (3H), 2.70-3.24 (2H), 3.28 (3H), 3.36-3.43 (2H),3.44-3.49 (2H), 4.37 (4H), 7.19 (1H), 7.43 (1H), 7.49-7.62 (3H),7.90-8.03 (2H), 8.08-8.25 (2H), 8.52 (1H).

Example 338N-(2-methoxyethyl)-4-methyl-2-({1-[(1-methyl-1H-benzimidazol-2-yl)carbonyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 39 mg of the title compound wasobtained from 100 mg of 71a and 80 mg of1-methyl-1H-benzimidazol-2-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.22-1.43 (2H), 1.43-1.53 (1H),1.59-1.70 (1H), 2.27-2.44 (1H), 2.53 (3H), 2.87 (1H), 3.11 (1H), 3.28(3H), 3.36-3.42 (2H), 3.43-3.48 (2H), 3.83 (3H), 4.00-4.14 (1H), 4.39(2H), 4.48-4.61 (1H), 7.18 (1H), 7.23-7.46 (3H), 7.58-7.74 (2H),8.10-8.20 (1H), 8.53 (1H).

Example 339N-(2-methoxyethyl)-4-methyl-2-({1-[(2-phenyloxazol-5-yl)carbonyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 30 mg of the title compound wasobtained from 100 mg of 71a and 86 mg of 2-phenyloxazol-5-carboxylicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.14-1.48 (2H), 1.59 (2H), 2.24-2.46(1H), 2.52-2.56 (3H), 2.71-3.01 (1H), 3.11-3.26 (1H), 3.28 (3H),3.36-3.43 (2H), 3.43-3.50 (2H), 4.38 (4H), 7.19 (1H), 7.43 (1H),7.52-7.67 (3H), 7.80 (1H), 7.97-8.05 (2H), 8.16 (1H), 8.53 (1H).

Example 3402-{[1-(benzoxazol-2-ylcarbonyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 37 mg of the title compound wasobtained from 100 mg of 71a and 84 mg of benzoxazol-2-carboxylic acid inDMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.19-1.43 (2H), 1.48-1.73 (2H),2.28-2.45 (1H), 2.53 (3H), 2.91 (1H), 3.22 (1H), 3.33-3.57 (m, 7H),4.25-4.60 (4H), 7.18 (1H), 7.36-7.62 (3H), 7.78-7.95 (2H), 8.16 (1H),8.53 (1H).

Example 3412-({1-[4-(1-cyano-1-methylethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 20 mg of the title compound wasobtained from 100 mg of 71a and 86 mg of4-(1-cyano-1-methylethyl)benzoic acid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.17-1.34 (2H), 1.35-1.64 (2H), 1.70(6H), 2.16-2.40 (1H), 2.52 (3H), 2.64-3.13 (2H), 3.28 (3H), 3.40 (2H),3.43-3.49 (2H), 3.49-3.67 (1H), 4.35 (3H), 7.18 (1H), 7.42 (3H), 7.58(2H), 8.15 (1H), 8.50 (1H).

Example 342N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 37 mg of the title compound wasobtained from 100 mg of 71a and 98 mg of 4-(2-pyrimidinyloxy)benzoicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.26 (2H), 1.38-1.66 (2H), 2.20-2.40(1H), 2.52-2.56 (3H), 2.70-3.16 (2H), 3.28 (3H), 3.36-3.43 (2H),3.43-3.49 (2H), 3.64-3.77 (m, 1H), 4.36 (3H), 7.18 (1H), 7.22-7.33 (3H),7.39-7.49 (3H), 8.15 (1H), 8.43-8.57 (1H), 8.66 (2H).

Example 343N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-3-yloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 7 mg of the title compound wasobtained from 75 mg of 71a and 73 mg of 4-(3-pyridyloxy)benzoic acid inDMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.17-1.32 (2H), 1.35-1.69 (2H),2.19-2.38 (1H), 2.52 (3H), 2.70-3.14 (2H), 3.28 (3H), 3.34-3.43 (2H),3.43-3.51 (2H), 3.55-3.70 (1H), 4.35 (3H), 7.04-7.13 (2H), 7.18 (1H),7.37-7.46 (3H), 7.47-7.54 (1H), 7.58 (1H), 8.15 (1H), 8.38-8.55 (3H).

Example 344N-(2-methoxyethyl)-2-{[1-(7-methoxy-2-naphthoyl)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 28 mg of the title compound wasobtained from 75 mg of 71a and 69 mg of the carboxylic acid prepared inExample 344c) in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.21-1.35 (2H), 1.37-1.75 (2H),2.23-2.39 (1H), 2.52 (3H), 2.73-3.13 (2H), 3.28 (3H), 3.35-3.42 (2H),3.45 (2H), 3.53-3.74 (1H), 3.88 (3H), 4.37 (3H), 7.13-7.25 (2H), 7.29(1H), 7.36-7.48 (2H), 7.77-7.93 (3H), 8.15 (1H), 8.52 (1H).

The starting material was prepared as follows:

Example 344a7-methoxynaphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutan-1-sulphonate

5.12 g of 7-methoxy-2-naphthol were dissolved in 50 ml toluene andcooled to 0° C. 30.7 ml of N,N-diisopropylethylamine and 17.6 ml ofnonafluorobutanesulphonyl fluoride were successively added dropwise tothis and the reaction mixture was then stirred at room temperature untilcomplete conversion. The reaction mixture was poured into 600 ml ofsaturated ammonium chloride solution, the deposited brown oil separatedand the aqueous phase extracted several times with ethyl acetate. Thecombined organic phases were washed with water and saturated sodiumchloride solution, dried and concentrated. The residue was purified bycolumn chromatography on silica gel using a hexane/ethyl acetategradient. Yield: 11.45 g of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 3.89 (3H), 7.28 (1H), 7.41 (1H),7.52 (1H), 7.90-8.00 (2H), 8.05 (1H).

Example 344b Methyl 7-methoxynaphthalen-2-carboxylate

Analogously to Example 1e, 2.34 g of the title compound was obtainedfrom 11.0 g of 344a and 8.8 ml of methanol.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 3.89 (3H), 3.91 (3H), 7.31 (1H),7.57 (1H), 7.82 (1H), 7.94 (2H), 8.54 (1H).

Example 344c 7-methoxynaphthalen-2-carboxylic acid

Analogously to Example 258d, 1.27 g of the title compound was obtainedfrom 2.0 g of 344b.

¹H-NMR (300 MHz, DMSO-d6): δ [ppm], 3.89 (3H), 7.30 (1H), 7.53 (1H),7.78-7.86 (1H), 7.87-8.01 (2H), 8.50 (1H), 12.99 (1H).

Example 345N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 221 mg of the title compound wasobtained from 200 mg of 71a and 232 mg of4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.21-1.34 (2H), 1.36-1.72 (2H),2.23-2.39 (1H), 2.53 (3H), 2.89 (2H), 3.31 (3H), 3.36-3.43 (2H),3.43-3.50 (2H), 3.53-3.86 (1H), 4.36 (3H), 7.18 (1H), 7.23-7.33 (3H),7.37-7.50 (3H), 8.13 (1H), 8.25 (1H), 8.51 (1H), 8.55-8.63 (1H).

Example 346N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 29 mg of the title compound wasobtained from 100 mg of 71a and 98 mg of 4-(2-pyridyloxy)benzoic acid inDMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.39-1.68 (2H), 2.24-2.39(1H), 2.52-2.56 (3H), 2.71-3.13 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.45(2H), 3.53-3.87 (1H), 4.36 (3H), 7.08 (1H), 7.13-7.26 (4H), 7.34-7.52(3H), 7.88 (1H), 8.07-8.23 (2H), 8.51 (1H).

Example 347N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[4-(trifluoromethyl)pyrimidin-2-yl]-oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 11 mg of the title compound wasobtained from 75 mg of 71a and 97 mg of4-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.37-1.69 (2H), 2.19-2.39(1H), 2.53 (3H), 2.68-3.18 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.45 (2H),3.51-3.79 (1H), 4.36 (3H), 7.18 (1H), 7.31-7.39 (2H), 7.39-7.53 (3H),7.81 (1H), 8.15 (1H), 8.51 (1H), 9.00 (1H).

Example 3482-{[1-(benzothiazol-2-ylcarbonyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 28 mg of the title compound wasobtained from 75 mg of 71a and 61 mg of benzothiazol-2-carboxylic acidin DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.34 (2H), 1.62 (2H), 2.32-2.45(1H), 2.53 (3H), 2.82-3.00 (1H), 3.26 (1H), 3.28 (3H), 3.40 (2H),3.43-3.50 (2H), 4.38 (3H), 4.98-5.23 (1H), 7.19 (1H), 7.43 (1H), 7.59(2H), 8.01-8.30 (3H), 8.53 (1H).

Example 349N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 34 mg of the title compound wasobtained from 75 mg of 71a and 96 mg of 303b in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.24 (2H), 1.37-1.68 (2H), 2.22-2.38(1H), 2.53 (3H), 2.71-3.14 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.44-3.49(2H), 3.52-3.84 (1H), 4.36 (3H), 7.09-7.29 (3H), 7.35-7.53 (3H), 7.65(1H), 7.92 (1H), 8.13 (1H), 8.51 (1H), 8.60 (1H).

Example 350N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 36 mg of the title compound wasobtained from 100 mg of 71a and 129 mg of4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.20-1.34 (2H), 1.36-1.66 (2H),2.24-2.39 (1H), 2.53 (3H), 2.70-3.16 (2H), 3.28 (3H), 3.36-3.43 (2H),3.44-3.49 (2H), 3.53-3.82 (1H), 4.36 (3H), 7.18 (1H), 7.22-7.30 (2H),7.32-7.50 (4H), 7.67 (1H), 8.06-8.21 (2H), 8.51 (1H).

Example 3512-({1-[(4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 15 mg of the title compound wasobtained from 100 mg of 71a and 104 mg of4′-methoxy-biphenyl-4-carboxylic acid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.24 (2H), 1.37-1.64 (2H), 2.19-2.32(1H), 2.53 (3H), 2.74-3.10 (2H), 3.28 (3H), 3.40 (2H), 3.45 (2H),3.67-3.91 (4H), 4.21-4.64 (3H), 7.04 (2H), 7.19 (1H), 7.41 (2H), 7.66(5H), 8.04-8.22 (1H), 8.51 (1H).

Example 352N-(2-methoxyethyl)-4-methyl-2-({1-[(3-phenyl-1,2,4-oxadiazol-5-yl)carbonyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 12 mg of the title compound wasobtained from 100 mg of 71a and 78 mg of3-phenyl-1,2,4-oxadiazol-5-carboxylic acid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.33 (2H), 1.50-1.72 (2H), 2.31-2.45(1H), 2.53 (3H), 2.86-3.04 (1H), 3.16-3.26 (1H), 3.28 (3H), 3.41 (2H),3.43-3.51 (2H), 3.94-4.13 (1H), 4.28-4.55 (3H), 7.19 (1H), 7.43 (1H),7.52-7.72 (3H), 7.96-8.09 (2H), 8.13 (1H), 8.52 (1H).

Example 353N-(2-methoxyethyl)-4-methyl-2-({1-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)-benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 21 mg of the title compound wasobtained from 100 mg of 71a and 91 mg of4-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.38-1.70 (4H), 1.97(2H), 2.18-2.41 (1H), 2.53 (3H), 2.75-3.02 (2H), 3.28 (3H), 3.35-3.54(8H), 3.84 (2H), 4.35 (2H), 4.52-4.77 (1H), 7.00 (2H), 7.18 (1H), 7.30(2H), 7.42 (1H), 8.13 (1H), 8.50 (1H).

Example 354N-(2-methoxyethyl)-4-methyl-2-({1-[(5-phenyloxazol-2-yl)carbonyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 10 mg of the title compound wasobtained from 100 mg of 71a and 77 mg of 5-phenyl-oxazol-2-carboxylicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.17-1.41 (2H), 1.59 (2H), 2.28-2.45(1H), 2.52-2.56 (3H), 2.85 (1H), 3.20 (1H), 3.28 (3H), 3.36-3.43 (2H),3.44-3.50 (2H), 4.38 (3H), 4.57-4.74 (1H), 7.19 (1H), 7.39-7.57 (4H),7.74-7.82 (2H), 7.88 (1H), 8.13 (1H), 8.52 (1H).

Example 355N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 40 mg of the title compound wasobtained from 100 mg of 71a and 115 mg of4-[(3-(trifluoromethyl)phenoxy]benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.35-1.65 (2H), 2.19-2.38(1H), 2.52-2.56 (3H), 2.71-3.12 (2H), 3.28 (3H), 3.36-3.43 (2H),3.43-3.50 (2H), 3.53-3.87 (1H), 4.35 (3H), 7.07-7.15 (2H), 7.18 (1H),7.30-7.48 (5H), 7.54 (1H), 7.64 (1H), 8.13 (1H), 8.50 (1H).

Example 3562-[(1-{4-[(5-cyanopyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 15 mg of the title compound wasobtained from 100 mg of 71a and 98 mg of4-[(5-cyanopyridin-2-yl)oxy]benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.21-1.35 (2H), 1.36-1.75 (2H),2.23-2.39 (1H), 2.53 (3H), 2.69-3.19 (2H), 3.28 (3H), 3.36-3.43 (2H),3.46 (2H), 3.53-3.85 (1H), 4.36 (3H), 7.18 (1H), 7.23-7.33 (3H),7.36-7.53 (3H), 8.13 (1H), 8.34 (1H), 8.51 (1H), 8.66 (1H).

Example 3572-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 40 mg of the title compound wasobtained from 100 mg of 71a and 102 mg of4-[(5-chloropyridin-2-yl)oxy]benzoic acid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.25 (2H), 1.36-1.70 (2H), 2.20-2.39(1H), 2.53 (3H), 2.66-3.15 (2H), 3.28 (3H), 3.40 (2H), 3.43-3.50 (2H),3.55-3.90 (1H), 4.36 (3H), 7.08-7.28 (4H), 7.42 (3H), 7.99 (1H),8.10-8.30 (2H), 8.51 (1H).

Example 3582-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 22 mg of the title compound wasobtained from 100 mg of 71a and 102 mg of 4-(2,4-difluorophenoxy)benzoicacid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.21 (2H), 1.33-1.76 (2H), 2.20-2.39(1H), 2.52 (3H), 2.69-3.13 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50(2H), 3.53-3.90 (1H), 4.35 (3H), 6.91-7.04 (2H), 7.11-7.22 (2H),7.30-7.46 (4H), 7.51 (1H), 8.13 (1H), 8.50 (1H).

Example 3592-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 23 mg of the title compound wasobtained from 100 mg of 71a and 102 mg of 4-(3,4-difluorophenoxy)benzoicacid in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.17-1.30 (2H), 1.35-1.70 (2H),2.20-2.40 (1H), 2.52 (3H), 2.74-3.14 (2H), 3.28 (3H), 3.40 (2H),3.43-3.51 (2H), 3.52-3.89 (1H), 4.35 (3H), 6.94 (1H), 7.05 (2H), 7.18(1H), 7.30 (1H), 7.36-7.59 (4H), 8.15 (1H), 8.51 (1H).

Example 360N-(2-methoxyethyl)-4-methyl-2-[(1-{[4′-(trifluoromethyl)biphenyl-4-yl]-carbonyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 44 mg of the title compound wasobtained from 100 mg of 71a and 109 mg of4′-(trifluoromethyl)biphenyl-4-carboxylic acid in DMF

LC-MS: R_(t)=1.28 min, MS (ES+): m/z=579 (M+H)⁺.

Example 3612-({1-[4-(3-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 43 mg of the title compound wasobtained from 100 mg of 71a and 95 mg of 4-(3-fluorophenoxy)benzoic acidin DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.17-1.31 (2H), 1.33-1.69 (2H),2.19-2.38 (1H), 2.52 (3H), 2.70-3.11 (2H), 3.28 (3H), 3.36-3.43 (2H),3.43-3.49 (2H), 3.54-3.85 (1H), 4.35 (3H), 6.85-7.13 (5H), 7.18 (1H),7.35-7.55 (4H), 8.15 (1H), 8.51 (1H).

Example 3622-{[1-(2-fluoro-4-isopropoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 31 mg of the title compound wasobtained from 75 mg of 71a and 41 mg of 2-fluoro-4-isopropoxybenzoicacid.

¹H-NMR (300 MHz, chloroform-d): δ [ppm], 1.21-1.42 (8H), 1.51 (1H), 1.69(1H), 2.38 (1H), 2.56-2.80 (4H), 2.87-3.08 (1H), 3.36 (3H), 3.48-3.73(4H), 4.28 (2H), 4.51 (1H), 4.74 (1H), 5.28 (1H), 6.19 (1H), 6.54 (1H),6.67 (1H), 7.13-7.38 (2H), 7.50 (1H), 7.94 (1H).

Example 3632-({1-[(3-fluoro-3′,4′-dimethylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 35 mg of the title compound wasobtained from 75 mg of 71a and 50 mg of3-fluoro-3′,4′-dimethylbiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, chloroform-d): δ [ppm], 1.25-1.51 (2H), 1.57 (1H), 1.76(1H), 2.25-2.37 (6H), 2.45 (1H), 2.61-2.71 (3H), 2.79 (1H), 3.06 (1H),3.40 (3H), 3.53-3.77 (5H), 4.34 (2H), 4.83 (1H), 6.04-6.30 (1H),7.15-7.47 (7H), 7.55 (1H), 7.98 (1H).

Example 3642-({1-[(2′,3-difluoro-4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 28 mg of the title compound wasobtained from 90 mg of 71a and 65 mg of3,2′-difluoro-4′-methoxybiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, chloroform-d): δ [ppm], 1.25-1.50 (2H), 1.50-1.84 (2H),2.44 (1H), 2.66 (3H), 2.78 (1H), 3.03 (1H), 3.39 (3H), 3.53-3.76 (5H),3.85 (3H), 4.23-4.45 (2H), 4.83 (1H), 6.17 (1H), 6.64-6.92 (2H),7.18-7.48 (5H), 7.54 (1H), 7.97 (1H).

Example 3652-({1-[4-(difluoromethoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 23 mg of the title compound wasobtained from 75 mg of 71a and 38 mg of 4-(difluoromethoxy)benzoic acid.

¹H-NMR (300 MHz, chloroform-d): δ [ppm], 1.26 (2H), 1.59 (2H), 2.26-2.49(1H), 2.62 (3H), 2.84 (2H), 3.36 (3H), 3.43 (1H), 3.50-3.96 (4H), 4.29(2H), 4.46-5.02 (1H), 6.13-6.25 (1H), 6.26-6.82 (1H), 7.11 (2H),7.22-7.43 (3H), 7.50 (1H), 7.93 (1H).

Example 3662-({1-[4-(2-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

120 mg of compound 54, 26 mg of o-fluorophenol, 152 mg of caesiumcarbonate, 6.7 mg of copper(I) bromide and 3.2 mg of (2-pyridyl)acetonewere suspended in 6 ml dimethyl sulphoxide and stirred for 3 days at 80°C. The reaction mixture was filtered, the filter cake washed with waterand ethyl acetate, and the aqueous phase extracted several times withethyl acetate. The combined organic phases were dried with sodiumsulphate and concentrated. The residue was purified by HPLC and 12 mg ofthe title compound was obtained.

¹H-NMR (300 MHz, chloroform-d): δ [ppm], 1.16-1.47 (2H), 1.62 (2H), 2.43(1H), 2.66 (3H), 2.85 (2H), 3.39 (3H), 3.53-3.74 (4H), 3.79-4.19 (1H),4.33 (2H), 4.47-5.02 (1H), 6.15 (1H), 6.96 (2H), 7.07-7.23 (3H),7.30-7.45 (3H), 7.54 (1H), 7.96 (1H).

Example 3672-({1-[(4′-cyano-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 40 mg of the title compound was obtainedfrom 80 mg of 54 and 38 mg of (2-methyl-4-cyanophenyl)boronic acid underreflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.20-1.34 (2H), 1.36-1.69 (2H), 2.28(4H), 2.53 (3H), 2.69-3.19 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50(2H), 3.54-3.77 (1H), 4.37 (3H), 7.18 (1H), 7.37-7.50 (6H), 7.74 (1H),7.83 (1H), 8.15 (1H), 8.52 (1H).

Example 3682-({1-[4-(5-chloropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

200 mg of the aryl bromide prepared in Example 54 together with 187 mgof (5-chloropyridin-2-yl)-2-boronic acid pinacol ester were first placedin 3 ml DMF, treated with 48 mg of1,1′-bis(diphenylphosphino)ferrocenodichloropalladium(II), 39 mg ofcopper(I)chloride 254 mg of caesium carbonate and 22 mg of1,1′-bis(diphenylphosphino)ferrocene and heated for ca. 1 day at 70° C.,until further progress of the reaction could no longer be observed. Thereaction mixture was treated with water and saturated sodium hydrogencarbonate solution, treated several times with ethyl acetate, and thecombined organic phases dried with sodium sulphate and concentrated.After HPLC purification, this yielded 92 mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.19-1.36 (2H), 1.37-1.72 (2H),2.23-2.41 (1H), 2.52-2.57 (3H), 2.70-3.13 (2H), 3.28 (3H), 3.39 (2H),3.45 (2H), 3.51-3.80 (1H), 4.36 (3H), 7.18 (1H), 7.36-7.52 (3H), 8.05(2H), 8.09-8.22 (3H), 8.51 (1H), 8.73 (1H).

Example 369N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 317, 33 mg of the title compound was obtainedfrom 100 mg of 54 and 80 mg of [6-(trifluoromethyl)pyridin-2-yl]boronicacid pinacol ester under reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.18-1.35 (2H), 1.36-1.67 (2H),2.25-2.41 (1H), 2.53 (3H), 2.70-3.15 (2H), 3.28 (3H), 3.35-3.43 (2H),3.43-3.51 (2H), 3.53-3.73 (1H), 4.37 (3H), 7.18 (1H), 7.42 (1H), 7.53(2H), 7.89 (1H), 8.06-8.26 (4H), 8.33 (1H), 8.51 (1H).

Example 370N-(2-methoxyethyl)-2-({1-[(4′-methoxy-2′-methylbiphenyl-4-yl)carbonyl]-piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 52 mg of the title compound was obtainedfrom 100 mg of 54 and 48 mg of (4-methoxy-2-methylphenyl)boronic acidunder reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.16-1.35 (2H), 1.37-1.67 (2H), 2.23(3H), 2.26-2.42 (1H), 2.53 (3H), 2.70-3.12 (2H), 3.28 (3H), 3.36-3.43(2H), 3.43-3.50 (2H), 3.77 (4H), 4.36 (3H), 6.77-6.92 (2H), 7.10-7.22(2H), 7.39 (5H), 8.15 (1H), 8.52 (1H).

Example 3712-({1-[(4′-chloro-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 43 mg of the title compound was obtainedfrom 100 mg of 54 and 50 mg of (4-chloro-2-methylphenyl)boronic acidunder reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.27 (2H), 1.38-1.70 (2H), 2.23(4H), 2.53 (3H), 2.70-3.15 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.49(2H), 3.55-3.84 (1H), 4.36 (3H), 7.12-7.27 (2H), 7.28-7.35 (1H),7.36-7.47 (6H), 8.15 (1H), 8.52 (1H).

Example 3722-[(1-{[4′-(2-cyanopropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)-methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 67 mg of the title compound was obtainedfrom 100 mg of 54 and 55 mg of [4-(1-cyano-1-methylethyl)phenyl]boronicacid under reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.28 (2H), 1.36-1.65 (2H), 1.72(6H), 2.24-2.40 (1H), 2.53 (3H), 2.70-3.14 (2H), 3.28 (3H), 3.36-3.43(2H), 3.43-3.49 (2H), 3.54-3.77 (1H), 4.36 (3H), 7.18 (1H), 7.38-7.50(3H), 7.62 (2H), 7.75 (4H), 8.15 (1H), 8.52 (1H).

Example 373N-(2-methoxyethyl)-2-({1-[4-(5-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}-methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 368, 12 mg of the title compound was obtainedfrom 200 mg of 54 and 183 mg of (5-methoxypyridin-2-yl)boronic acidpinacol ester under reflux.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm], 1.22-1.33 (2H), 1.36-1.66 (2H),2.23-2.38 (1H), 2.53 (3H), 2.68-3.12 (2H), 3.28 (3H), 3.35-3.42 (2H),3.43-3.50 (2H), 3.54-3.78 (1H), 3.88 (3H), 4.36 (3H), 7.18 (1H),7.36-7.55 (4H), 7.96 (1H), 8.07 (2H), 8.13 (1H), 8.39 (1H), 8.51 (1H).

Example 374N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 317, 37 mg of the title compound was obtainedfrom 100 mg of 54 and 56 mg of [2-(trifluoromethyl)pyridin-5-yl]boronicacid under reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.19-1.36 (2H), 1.36-1.69 (2H),2.21-2.42 (1H), 2.53 (3H), 2.70-3.14 (2H), 3.28 (3H), 3.36-3.43 (2H),3.43-3.50 (2H), 3.53-3.72 (1H), 4.36 (3H), 7.18 (1H), 7.42 (1H), 7.53(2H), 7.89 (2H), 8.01 (1H), 8.15 (1H), 8.41 (1H), 8.52 (1H), 9.13 (1H).

Example 375N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-3-yl)benzoyl]piperidin-4-yl}-methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 50 mg of the title compound was obtainedfrom 100 mg of 54 and 47 mg of (2-methoxypyridin-5-yl)boronic acid underreflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.26 (2H), 1.34-1.70 (2H), 2.21-2.40(1H), 2.53 (3H), 2.69-3.15 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.49(2H), 3.51-3.79 (1H), 3.90 (3H), 4.36 (3H), 6.93 (1H), 7.18 (1H),7.36-7.52 (3H), 7.72 (2H), 8.05 (1H), 8.15 (1H), 8.46-8.57 (2H).

Example 3762-({1-[(4′-fluoro-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 261 mg of the title compound was obtainedfrom 300 mg of 54 and 135 mg of (4-fluoro-2-methylphenyl)boronic acidunder reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.27 (2H), 1.37-1.70 (2H), 2.24(4H), 2.53 (3H), 2.71-3.14 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50(2H), 3.55-3.83 (1H), 4.37 (3H), 7.05-7.12 (1H), 7.18 (2H), 7.22-7.30(1H), 7.40 (5H), 8.14 (1H), 8.52 (1H).

Example 377N-(2-methoxyethyl)-4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 45 mg of the title compound was obtainedfrom 80 mg of 54 and 32 mg of (2-methylpyridin-5-yl)boronic acid underreflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.26 (2H), 1.37-1.71 (2H), 2.18-2.39(1H), 2.52-2.58 (3H), 2.73-3.16 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.45(2H), 3.54-3.79 (1H), 4.36 (3H), 7.18 (1H), 7.30-7.54 (4H), 7.76 (2H),8.00 (1H), 8.15 (1H), 8.51 (1H), 8.78 (1H).

Example 378N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 30 mg of the title compound was obtainedfrom 100 mg of 54 and 45 mg of (6-methoxypyridin-2-yl)boronic acid underreflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.26 (2H), 1.35-1.68 (2H), 2.32(1H), 2.52 (3H), 2.70-3.13 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50(2H), 3.53-3.74 (1H), 3.96 (3H), 4.36 (3H), 6.81 (1H), 7.18 (1H),7.37-7.67 (4H), 7.81 (1H), 8.15 (3H), 8.51 (1H).

Example 379N-(2-methoxyethyl)-4-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzoyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 36 mg of the title compound was obtainedfrom 100 mg of 54 and 64 mg of (2-methylpyrimidin-5-yl)boronic acidpinacol ester under reflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.27 (2H), 1.38-1.70 (2H), 2.21-2.40(1H), 2.53 (3H), 2.67 (3H), 2.73-3.16 (2H), 3.28 (3H), 3.40 (2H),3.43-3.50 (2H), 3.53-3.76 (1H), 4.36 (3H), 7.18 (1H), 7.42 (1H), 7.51(2H), 7.84 (2H), 8.13 (1H), 8.51 (1H), 9.05 (2H).

Example 3802-({1-[(4′-fluoro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 47 mg of the title compound was obtainedfrom 100 mg of 54 and 50 mg of (4-fluoro-2-methoxyphenyl)boronic acidunder reflux.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm], 1.19-1.34 (2H), 1.37-1.71 (2H),2.22-2.40 (1H), 2.53 (3H), 2.70-3.15 (2H), 3.28 (3H), 3.36-3.43 (2H),3.43-3.50 (2H), 3.56-3.75 (1H), 3.79 (3H), 4.36 (3H), 6.87 (1H),6.99-7.10 (1H), 7.18 (1H), 7.30-7.46 (4H), 7.50 (2H), 8.13 (1H), 8.51(1H).

Example 3812-({1-[(4′-chloro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 87 mg of the title compound was obtainedfrom 100 mg of 54 and 54 mg of (4-fluoro-2-methoxyphenyl)boronic acidunder reflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=1.26 (2H), 1.39-1.69 (2H), 2.19-2.39(1H), 2.53 (3H), 2.75-3.14 (2H), 3.28 (3H), 3.40 (2H), 3.45 (2H),3.57-3.74 (1H), 3.81 (3H), 4.36 (3H), 7.04-7.25 (3H), 7.28-7.62 (6H),8.13 (1H), 8.51 (1H).

Example 382N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 317, 14 mg of the title compound was obtainedfrom 100 mg of 54 and 56 mg of[2-(trifluoromethyl)pyrimidin-5-yl]boronic acid under reflux.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm], 1.24 (2H), 1.38-1.73 (2H), 2.22-2.41(1H), 2.53 (3H), 2.70-2.89 (1H), 2.94-3.18 (1H), 3.28 (3H), 3.36-3.43(2H), 3.44-3.49 (2H), 3.51-3.70 (1H), 4.37 (3H), 7.18 (1H), 7.42 (1H),7.57 (2H), 7.97 (2H), 8.13 (1H), 8.51 (1H), 9.43 (2H).

Example 3832-({1-[(4′-chloro-2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 51 mg of the title compound was obtainedfrom 100 mg of 54 and 51 mg of (4-chloro-2-fluorophenyl)boronic acidunder reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.27 (2H), 1.38-1.68 (2H), 2.32(1H), 2.53 (3H), 2.71-2.91 (1H), 2.93-3.16 (1H), 3.28 (3H), 3.40 (2H),3.45 (2H), 3.53-3.78 (m, 1H), 4.37 (3H), 7.18 (1H), 7.33-7.52 (4H),7.53-7.74 (4H), 8.13 (1H), 8.51 (1H).

Example 3842-({1-[(2′-chloro-4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 26 mg of the title compound was obtainedfrom 100 mg of 54 and 51 mg of (2-chloro-4-fluorophenyl)boronic acidunder reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.28 (2H), 1.38-1.67 (2H), 2.23-2.39(1H), 2.53 (3H), 2.71-2.91 (1H), 2.94-3.15 (1H), 3.28 (3H), 3.36-3.43(2H), 3.43-3.50 (2H), 3.54-3.74 (1H), 4.37 (3H), 7.18 (1H), 7.33 (1H),7.39-7.63 (7H), 8.13 (1H), 8.51 (1H).

Example 3852-({1-[4-(5-chloropyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 22 mg of the title compound was obtainedfrom 100 mg of 54 and 46 mg of (5-chloropyridin-3-yl)boronic acid underreflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.21-1.35 (2H), 1.36-1.69 (2H),2.23-2.40 (1H), 2.53 (3H), 2.69-2.90 (1H), 2.92-3.16 (1H), 3.28 (3H),3.40 (2H), 3.45 (2H), 3.53-3.73 (1H), 4.36 (3H), 7.18 (1H), 7.35-7.57(3H), 7.86 (2H), 8.15 (1H), 8.30 (1H), 8.52 (1H), 8.65 (1H), 8.90 (1H).

Example 3862-({1-[4-(5-fluoropyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 57 mg of the title compound was obtainedfrom 100 mg of 54 and 41 mg of (5-fluoropyridin-3-yl)boronic acid underreflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.27 (2H), 1.37-1.70 (2H), 2.24-2.40(1H), 2.52-2.55 (3H), 2.70-2.89 (1H), 2.93-3.15 (1H), 3.28 (3H),3.36-3.43 (2H), 3.43-3.50 (2H), 3.53-3.73 (1H), 4.36 (3H), 7.18 (1H),7.42 (1H), 7.50 (2H), 7.86 (2H), 8.07-8.18 (2H), 8.51 (1H), 8.61 (1H),8.84 (1H).

Example 387N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[5-(trifluoromethyl)pyridin-3-yl]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 317, 73 mg of the title compound was obtainedfrom 100 mg of 54 and 56 mg of [5-(trifluoromethyl)pyridin-3-yl]boronicacid under reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.20-1.35 (2H), 1.36-1.67 (2H),2.23-2.40 (1H), 2.53 (3H), 2.69-2.92 (1H), 2.93-3.17 (1H), 3.28 (3H),3.35-3.43 (2H), 3.43-3.49 (2H), 3.53-3.75 (1H), 4.37 (3H), 7.18 (1H),7.42 (1H), 7.52 (2H), 7.93 (2H), 8.07-8.20 (1H), 8.45-8.58 (2H), 9.00(1H), 9.24 (1H).

Example 3882-[(1-{[4′-(2-hydroxypropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)-methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 46 mg of the title compound was obtainedfrom 100 mg of 54 and 77 mg of (4-hydroxy-tert-butylphenyl)boronic acidpinacol ester under reflux.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.26 (2H), 1.45 (8H), 2.22-2.42(1H), 2.53 (3H), 2.71-2.90 (1H), 2.91-3.14 (1H), 3.28 (3H), 3.40 (2H),3.43-3.50 (2H), 3.56-3.80 (1H), 4.36 (3H), 5.06 (1H), 7.18 (d, 1H),7.37-7.50 (3H), 7.50-7.67 (4H), 7.71 (2H), 8.15 (1H), 8.52 (1H).

Example 3892-({1-[(3′,5′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 22 mg of the title compound was obtainedfrom 100 mg of 54 and 46 mg of (3,5-difluorophenyl)boronic acid underreflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.18-1.35 (2H), 1.36-1.70 (2H),2.19-2.39 (1H), 2.52-2.56 (3H), 2.71-2.92 (1H), 2.93-3.17 (1H), 3.28(3H), 3.36-3.43 (2H), 3.43-3.49 (2H), 3.52-3.71 (1H), 4.36 (3H),7.11-7.33 (2H), 7.37-7.54 (5H), 7.81 (2H), 8.13 (1H), 8.51 (1H).

Example 3902-({1-[(4′-fluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 25 mg of the title compound was obtainedfrom 60 mg of 332 and 19 mg of (4-fluorophenyl)boronic acid underreflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.25 (2H), 1.37-1.67 (2H), 2.24(4H), 2.53 (3H), 2.69-2.87 (1H), 2.92-3.14 (1H), 3.28 (3H), 3.36-3.43(2H), 3.43-3.50 (2H), 3.56-3.81 (1H), 4.36 (3H), 7.11-7.34 (6H),7.36-7.46 (3H), 8.15 (1H), 8.52 (1H).

Example 3912-({1-[(3′,5′-difluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 317, 30 mg of the title compound was obtainedfrom 60 mg of 332 and 27 mg of (3,5-difluorophenyl)boronic acid underreflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.36-1.69 (2H), 2.27(4H), 2.53 (3H), 2.69-2.90 (1H), 2.92-3.15 (1H), 3.28 (3H), 3.36-3.43(2H), 3.45 (2H), 3.53-3.76 (1H), 4.36 (3H), 7.08-7.21 (3H), 7.22-7.34(4H), 7.42 (1H), 8.15 (1H), 8.52 (1H).

Example 392N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(3-pyridyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 19 mg of the title compound was obtainedfrom 60 mg of 332 and 21 mg of pyridine-3-ylboronic acid under reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.20-1.33 (2H), 1.37-1.71 (2H), 2.26(4H), 2.53 (3H), 2.70-2.88 (1H), 2.94-3.17 (1H), 3.28 (3H), 3.36-3.43(2H), 3.43-3.49 (2H), 3.56-3.82 (1H), 4.36 (3H), 7.18 (1H), 7.23-7.37(3H), 7.39-7.56 (2H), 7.83 (1H), 8.15 (1H), 8.52 (1H), 8.56-8.65 (2H).

Example 393N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(4-pyridyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 19 mg of the title compound was obtainedfrom 60 mg of 332 and 21 mg of pyridine-4-ylboronic acid under reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.18-1.33 (2H), 1.37-1.67 (2H), 2.27(4H), 2.52-2.56 (3H), 2.70-2.86 (1H), 2.93-3.13 (1H), 3.28 (3H),3.36-3.43 (2H), 3.43-3.49 (2H), 3.55-3.75 (1H), 4.36 (3H), 7.18 (1H),7.23-7.36 (3H), 7.38-7.48 (3H), 8.15 (1H), 8.52 (1H), 8.60-8.69 (2H).

Example 394N-(2-methoxyethyl)-4-methyl-2-({1-[(2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 317, 57 mg of the title compound was obtainedfrom 60 mg of 332 and 21 mg of phenylboronic acid under reflux.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.19-1.34 (2H), 1.37-1.67 (2H), 2.25(4H), 2.53 (3H), 2.68-2.88 (1H), 2.92-3.17 (1H), 3.28 (3H), 3.36-3.43(2H), 3.45 (2H), 3.59-3.81 (1H), 4.36 (3H), 7.13-7.32 (4H), 7.33-7.50(6H), 8.15 (1H), 8.52 (1H).

Example 3952-{[1-(4-bromobenzoyl)piperidin-4-yl]methyl}-N-(2-mesylethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 383 mg of the title compound wasobtained from 1 g of 395b and 797 mg of 4-bromobenzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.21-1.32 (2H), 1.34-1.67 (2H),2.21-2.38 (1H), 2.55 (3H), 2.68-2.87 (1H), 3.05 (4H), 3.39 (2H),3.45-3.59 (1H), 3.66 (2H), 4.35 (3H), 7.23 (1H), 7.28-7.37 (2H), 7.43(1H), 7.59-7.70 (2H), 8.34 (1H), 8.52 (1H).

The starting material was prepared as follows:

Example 395a Tert-butyl4-({5-[N-(2-mesylethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)piperidin-1-carboxylate

Analogously to Example 266a, 1.26 g of the title compound was obtainedfrom 2.506 g of 1c and 3.022 g of 2-mesylethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.02-1.17 (2H), 1.34-1.54 (11H),2.08-2.24 (1H), 2.55 (3H), 2.73 (2H), 3.06 (3H), 3.34-3.47 (2H),3.57-3.76 (2H), 3.91 (2H), 4.32 (2H), 7.23 (1H), 7.43 (1H), 8.33 (1H),8.52 (1H).

Example 395bN-(2-mesylethyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 258b from 1.26 g of compound 395a, 1.29 g of thetitle compound was obtained, which was reacted without furtherpurification.

Example 396N-(2-mesylethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 30 mg of the title compound wasobtained from 80 mg of 395b and 90 mg of4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.19-1.35 (2H), 1.36-1.72 (2H),2.22-2.41 (1H), 2.55 (3H), 3.06 (5H), 3.39 (2H), 3.49-3.89 (3H), 4.37(3H), 7.20-7.32 (4H), 7.40-7.49 (3H), 8.25 (1H), 8.34 (1H), 8.53 (1H),8.58 (1H).

Example 397N-(2-mesylethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 30 mg of the title compound wasobtained from 80 mg of 395b and 90 mg of 303b in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.24 (2H), 1.35-1.70 (2H), 2.22-2.40(1H), 2.55 (3H), 3.06 (5H), 3.39 (2H), 3.55-3.75 (3H), 4.36 (3H),7.20-7.28 (3H), 7.40-7.49 (3H), 7.65 (1H), 7.92 (1H), 8.34 (1H), 8.53(1H), 8.60 (1H).

Example 3982-({1-[(2′,4′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-mesylethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 25 mg of the title compound wasobtained from 80 mg of 395b and 74 mg of2′,4′-difluoro-biphenyl-4-carboxylic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.21-1.35 (2H), 1.37-1.70 (2H),2.22-2.41 (1H), 2.55 (3H), 3.05 (5H), 3.38 (2H), 3.50-3.83 (3H), 4.37(3H), 7.15-7.29 (2H), 7.31-7.52 (4H), 7.55-7.73 (3H), 8.34 (1H), 8.53(1H).

Example 3992-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(3-hydroxy-3-methylbutyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 37 mg of the title compound wasobtained from 160 mg of 399b and 105 mg of 4-chlorobenzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.14 (6H), 1.17-1.32 (2H), 1.33-1.71(4H), 2.23-2.37 (1H), 2.51 (3H), 2.68-2.87 (1H), 2.87-3.13 (1H), 3.31(2H), 3.47-3.55 (1H), 4.34 (s, 4H), 7.17 (1H), 7.33-7.45 (3H), 7.50(2H), 7.97-8.09 (1H), 8.50 (1H).

The starting material was prepared as follows:

Example 399a Tert-butyl4-({5-[N-(3-hydroxy-3-methylbutyl)carbamoyl]-4-methyl-2H-indazol-2-yl}methyl)piperidin-1-carboxylate

Analogously to Example 1b, Version B, 150 mg of 1d and 69 mg of4-amino-2-methylbutan-2-ol in DMF were reacted at 60° C. After phaseseparation and extraction, the combined organic phases were additionallywashed with 0.1 N hydrochloric acid and saturated sodium hydrogencarbonate solution. This yielded 132 mg of the title compound, which wasused in the next step without further purification.

Example 399bN-(3-hydroxy-3-methylbutyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 258b, from 132 mg of 399a, 162 mg of the titlecompound was obtained, which was used in the next step without furtherpurification.

Example 4002-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-cyanoethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 55 mg of the title compound wasobtained from 177 mg of 400b and 128 mg of 4-chlorobenzoic acid in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.23 (2H), 1.33-1.70 (2H), 2.20-2.38(1H), 2.56 (3H), 2.78 (3H), 2.90-3.11 (1H), 3.47 (3H), 4.35 (3H), 7.22(1H), 7.34-7.56 (5H), 8.44-8.57 (2H).

The starting material was prepared as follows:

Example 400a Tert-butyl4-({5-[N-(2-cyanoethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)-piperidin-1-carboxylate

Analogously to Example 1b, Version B, 150 mg of 1d and 42 mg of3-aminopropannitrile in DMF were reacted at 60° C. After phaseseparation and extraction, the combined organic phases were additionallywashed with 0.1 N hydrochloric acid and saturated sodium hydrogencarbonate solution. This yielded 137 mg of the title compound, which wasused in the next step without further purification.

Example 400bN-(2-cyanoethyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 258b, from 137 mg of 400a 177 mg of the titlecompound was obtained, which was used in the next step without furtherpurification.

Example 4012-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(cyanomethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 75 mg of the title compound wasobtained from 90 mg of 238c and 29 mg of aminoacetonitrile in DMF.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.21-1.33 (23H), 1.34-1.69 (2H),2.15-2.41 (1H), 2.57 (3H), 2.75-2.86 (1H), 2.93-3.14 (1H), 3.39-3.69(1H), 4.29 (2H), 4.33-4.55 (3H), 7.18-7.28 (1H), 7.39 (2H), 7.43-7.55(3H), 8.57 (1H), 8.77-8.90 (1H).

Example 4022-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(cyclopropylmethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 44 mg of the title compound wasobtained from 90 mg of 238c) and 19 mg of cyclopropylmethylamine in DMF.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.23 (2H), 0.33-0.53 (2H), 0.94-1.11(1H), 1.20-1.33 (2H), 1.34-1.68 (2H), 2.21-2.41 (1H), 2.54 (3H),2.69-2.85 (1H), 2.93-3.08 (1H), 3.13 (2H), 3.44-3.68 (1H), 4.35 (3H),7.18 (1H), 7.33-7.46 (3H), 7.47-7.60 (2H), 8.07-8.30 (1H), 8.51 (1H).

Example 403N-(cyclobutylmethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 48 mg of the title compound wasobtained from 137 mg of 403b and 31 mg of (cyclobutylamino)methylaminehydrochloride.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.17-1.32 (2H), 1.35-1.64 (2H),1.67-1.90 (4H), 1.93-2.08 (2H), 2.22-2.38 (1H), 2.51-2.52 (3H),2.69-2.88 (1H), 2.90-3.13 (1H), 3.20-3.30 (2H), 3.51-3.83 (1H), 4.36(3H), 7.09-7.27 (5H), 7.35-7.52 (3H), 7.76 (2H), 8.13 (1H), 8.51 (1H).

The starting material was prepared as follows:

Example 403a Methyl4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazol-5-carboxylate

Analogously to Example 1b, Version B, 2.73 g of the title compound wasobtained from 3.76 g of 238a and 3.28 g of4-[4-(trifluoromethyl)phenoxy]benzoic acid.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.19-1.35 (2H), 1.38-1.74 (2H),2.17-2.41 (1H), 2.76 (3H), 2.78-3.14 (2H), 3.44-3.76 (1H), 3.82 (3H),4.37 (3H), 7.06-7.28 (4H), 7.38-7.50 (3H), 7.67 (1H), 7.76 (2H), 8.71(1H).

Example 403b4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)-methyl]-2H-indazol-5-carboxylicacid

Analogously to Example 1d, from 1.05 g of 403a, 970 mg of the titlecompound was obtained, which was used in the next step without furtherpurification.

Example 404N-isobutyl-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 35 mg of the title compound wasobtained from 100 mg of 403b and 14 mg of isobutylamine.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.91 (6H), 1.24 (2H), 1.34-1.69(2H), 1.82 (1H), 2.19-2.42 (1H), 2.52 (3H), 2.71-2.90 (1H), 3.06 (3H),3.51-3.85 (1H), 4.36 (3H), 7.05-7.27 (5H), 7.37-7.52 (3H), 7.76 (2H),8.16 (1H), 8.51 (1H).

Example 4054-methyl-N-neopentyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 36 mg of the title compound wasobtained from 100 mg of 403b and 16 mg of neopentylamine.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 0.92 (9H), 1.17-1.32 (2H), 1.34-1.69(2H), 2.21-2.38 (1H), 2.52-2.57 (3H), 2.70-2.88 (1H), 3.08 (3H),3.53-3.85 (1H), 4.36 (3H), 7.04-7.28 (5H), 7.35-7.52 (3H), 7.76 (2H),8.12 (1H), 8.51 (1H).

Example 406N-(cyclopropylmethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 33 mg of the title compound wasobtained from 100 mg of 403b and 26 mg of cyclopropylmethylamine.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 0.23 (2H), 0.35-0.54 (2H), 0.93-1.11(1H), 1.23 (2H), 1.36-1.67 (2H), 2.18-2.41 (1H), 2.54 (3H), 2.66-3.22(4H), 3.47-3.85 (1H), 4.36 (3H), 7.03-7.29 (5H), 7.35-7.53 (3H), 7.76(2H), 8.22 (1H), 8.52 (1H).

Example 407N-(2-cyanoethyl)-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}-methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 37 mg of the title compound wasobtained from 140 mg of 407a and 84 mg of 4′-fluorobiphenyl-4-carboxylicacid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.18-1.37 (2H), 1.37-1.68 (2H),2.22-2.41 (1H), 2.56 (3H), 2.78 (4H), 3.39-3.53 (2H), 3.56-3.82 (1H),4.37 (3H), 7.14-7.37 (3H), 7.39-7.53 (3H), 7.63-7.83 (4H), 8.36-8.60(2H).

The starting material was prepared as follows:

Example 407aN-(2-cyanoethyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 165 mg of 400a, 140 mg of the titlecompound was obtained, which was used in the next step without furtherpurification.

Example 4082-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-mesylethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b), Version B, 126 mg of the title compound wasobtained from 300 mg of 408a) and 156 mg of4′-fluorobiphenyl-4-carboxylic acid.

LC-MS: R_(t)=1.20 min, MS (ES+): m/z=577 (M+H)⁺.

The starting material was prepared as follows:

Example 408aN-(2-mesylethyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 346 mg of 395a, 300 mg of the titlecompound was obtained, which was used in the next step without furtherpurification.

Example 4092-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(3-hydroxypropyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 20 mg of the title compound wasobtained from 124 mg of 409b) and 73 mg of4′-fluorobiphenyl-4-carboxylic acid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.26 (2H), 1.38-1.59 (2H), 1.67(2H), 2.23-2.42 (1H), 2.52-2.57 (3H), 2.69-3.17 (2H), 3.19-3.94 (6H),4.36 (3H), 7.18 (1H), 7.31 (2H), 7.38-7.51 (3H), 7.63-7.86 (4H), 8.08(1H), 8.51 (1H).

The starting material was prepared as follows:

Example 409a Tert-butyl4-({5-[N-(3-hydroxypropyflcarbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)piperidin-1-carboxylate

Analogously to Example 1b, Version B, 151 mg of the title compound wasobtained from 150 mg of 1d and 30 mg of 3-amino-propan-1-ol.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.01-1.30 (3H), 1.32-1.49 (10H),1.67 (2H), 2.08-2.27 (1H), 2.52 (3H), 2.57-2.80 (2H), 3.29 (2H),3.41-3.54 (2H), 3.81-4.00 (2H), 4.32 (2H), 4.48 (1H), 7.18 (1H), 7.42(1H), 8.10 (1H), 8.50 (1H).

Example 409bN-(3-hydroxypropyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazol-5-carboxamide

Analogously to Example 1a, from 246 mg of 409a, 124 mg of the titlecompound was obtained, which was used in the next step without furtherpurification.

Example 4102-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-hydroxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 36 mg of the title compound wasobtained from 117 mg of 410b and 72 mg of 4′-fluorobiphenyl-4-carboxylicacid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.26 (2H), 1.39-1.74 (2H), 2.21-2.40(1H), 2.53 (3H), 2.75-3.16 (2H), 3.20-3.37 (2H), 3.43-3.74 (4H), 4.36(3H), 7.21 (1H), 7.31 (2H), 7.38-7.52 (3H), 7.65-7.81 (4H), 8.03 (1H),8.51 (1H).

The starting material was prepared as follows:

Example 410a Tert-butyl4-({5-[N-(2-hydroxyethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)piperidin-1-carboxylate

Analogously to Example 1b, Version B, 143 mg of the title compound wasobtained from 150 mg of 1d) and 25 mg of 2-aminoethan-1-ol.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.01-1.30 (3H), 1.32-1.51 (10H),2.07-2.26 (1H), 2.52-2.55 (3H), 2.58-2.82 (2H), 3.30 (2H), 3.45-3.58(2H), 3.83-3.98 (2H), 4.32 (2H), 4.69 (1H), 7.21 (1H), 7.41 (1H), 8.05(1H), 8.50 (1H).

Example 410bN-(3-hydroxypropyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazol-5-carboxamidehydrochloride

Analogously to Example 1a) from 138 mg of 410a, 117 mg of the titlecompound was obtained, which was used in the next step without furtherpurification.

Example 411(+/−)-N-(1,4-dioxan-2-ylmethyl)-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]-piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 62 mg of the title compound wasobtained from 226 mg of 411b) and 119 mg of4′-fluorobiphenyl-4-carboxylic acid.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 1.19-1.34 (2H), 1.37-1.73 (2H),2.23-2.42 (1H), 2.53 (3H), 2.69-2.90 (1H), 2.90-3.14 (1H), 3.17-3.30(3H), 3.47 (1H), 3.58 (1H), 3.59-3.70 (3H), 3.71-3.82 (2H), 4.37 (3H),7.19 (1H), 7.31 (2H), 7.38-7.53 (3H), 7.66-7.81 (4H), 8.18 (1H), 8.52(1H).

The starting material was prepared as follows:

Example 411a (+/−)-tert-butyl4-({5-[N-(1,4-dioxan-2-ylmethyl)carbamoyl]-4-methyl-2H-indazol-2-yl}methyl)piperidin-1-carboxylate

Analogously to Example 1b, Version B, 267 mg of the title compound wasobtained from 250 mg of 1d and 78 mg of(+/−)-1,4-dioxan-2-ylmethylamine.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm], 0.99-1.18 (2H), 1.38 (11H),2.09-2.24 (1H), 2.53 (3H), 3.10-3.29 (4H), 3.41-3.52 (1H), 3.53-3.70(4H), 3.70-3.81 (2H), 3.84-3.98 (2H), 4.32 (2H), 7.18 (1H), 7.41 (1H),8.12-8.24 (1H), 8.51 (1H).

Example 411b(+/−)-N-(1,4-dioxan-2-ylmethyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamidehydrochloride

Analogously to Example 1a, from 261 mg of 411a, 226 mg of the titlecompound was obtained, which was used in the next step without furtherpurification.

Example 412(+/−)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(oxetan-2-yl-methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 55 mg of the title compound wasobtained from 350 mg of 238c) and 83 mg of (+/−)-oxetan-2-ylmethylamine.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.16-1.31 (2H), 1.33-1.69 (2H),2.19-2.38 (2H), 2.53 (3H), 2.58-2.66 (1H), 2.66-2.86 (1H), 2.90-3.14(1H), 3.38-3.64 (3H), 4.35 (5H), 4.71-4.96 (1H), 7.19 (1H), 7.33-7.45(3H), 7.47-7.55 (2H), 8.21-8.37 (1H), 8.51 (1H).

Example 413(+/−)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(1,4-dioxan-2-ylmethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, Version B, 185 mg of the title compound wasobtained from 376 mg of 238c and 111 mg of(+/−)-1,4-dioxan-2-ylmethylamine hydrochloride.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm], 1.19-1.32 (2H), 1.33-1.66 (2H),2.20-2.40 (1H), 2.53 (3H), 2.71-2.86 (1H), 2.90-3.11 (1H), 3.16-3.32(3H), 3.40-3.59 (3H), 3.60-3.70 (2H), 3.71-3.83 (2H), 4.35 (3H), 7.18(1H), 7.31-7.46 (3H), 7.46-7.60 (2H), 8.21 (1H), 8.51 (1H).

Example 414 (R orS)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(1,4-dioxan-2-yl-methyl)-4-methyl-2H-indazole-5-carboxamide

From 185 mg of the racemate prepared in Example 413, 51 mg of the titlecompound together with 58 mg of the slower-eluting enantiomer (Example415) were obtained by racemate separation by means of preparative chiralHPLC (Method D).

Analytical chiral HPLC: 12.62 min

Example 415 (S orR)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(1,4-dioxan-2-yl-methyl)-4-methyl-2H-indazole-5-carboxamide

From 185 mg of the racemate prepared in Example 413, 58 mg of the titlecompound together with 51 mg of the faster-eluting enantiomer (Example414) were obtained by racemate separation by means of preparative chiralHPLC (Method D).

Analytical chiral HPLC: 13.68 min

Example 416 (R orS)-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

From 231 mg of the racemate prepared in Example 248, 24 mg of the titlecompound together with 24 mg of the slower-eluting enantiomer (Example417) were obtained by racemate separation by means of preparative chiralHPLC (Method E).

Analytical chiral HPLC: 7.08 min.

Example 417 (S orR)-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

From 231 mg of the racemate prepared in Example 248, 24 mg of the titlecompound together with 24 mg of the faster-eluting enantiomer (Example416) were obtained by racemate separation by means of preparative chiralHPLC (Method E).

Analytical chiral HPLC: 8.98 min.

Example 418 (R orS)—N-(1,4-dioxan-2-ylmethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)-phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

From 280 mg of the racemate prepared in Example 249, 65 mg of the titlecompound together with 75 mg of the slower-eluting enantiomer (Example419) were obtained by racemate separation by means of preparative chiralHPLC (Method D (injection volume: 0.1 ml; detection: UV 210 nM)).

Analytical chiral HPLC: 13.66 min

Example 419 (R orS)—N-(1,4-dioxan-2-ylmethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)-phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

From 280 mg of the racemate prepared in Example 249, 75 mg of the titlecompound together with 65 mg of the faster-eluting enantiomer (Example418) were obtained by racemate separation by means of preparative chiralHPLC (Method D (injection volume: 0.1 ml; Detection: UV 210 nM)).

Analytical chiral HPLC: 14.90 min

BIOLOGICAL EXAMPLES

The following biological examples which are described in sections 1-5and have only been carried out using EP2 receptor antagonists arealready contained in patent application PCT/EP2012/073556, unpublishedat the priority date of the present specification.

1. Detection of Antagonism to the Human Prostaglandin E2 (Subtype EP2)Receptor Signal

1.1 Detection Principle

The binding of PGE₂ to the EP2 subtype of the human PGE₂ receptorinduces the activation of membrane-located adenylate cyclases and leadsto the formation of cAMP. In the presence of the phosphodiesteraseinhibitor IBMX, the cAMP accumulated owing to this stimulation andreleased by cell lysis is used in a competitive detection method. Inthis test, the cAMP present in the lysate competes with afluorescence-labelled cAMP (cAMP-d2) for binding to an Eucryptate-labelled anti-cAMP antibody.

In the absence of cellular cAMP, a maximal signal is produced, which isattributable to the binding of this cAMP-d2 molecule to the antibody.After excitation of the cAMP-d2 molecule at 337 nm, there is afluorescence resonance energy transfer (FRET) to the Eu cryptatemolecules of the anti-cAMP antibody (labelled therewith), followed by along-lasting emission signal at 665 nm (and at 620 nM). Both signals aremeasured in a suitable measurement instrument with a time delay, i.e.after decay of the background fluorescence. Any increase in the low FRETsignal caused by prostaglandin E₂ administration (measured as well ratiochange=emission_(665nm)/emission_(620nm)*10000) indicates the action ofantagonists.

1.2. Detection Method

1.2.1. Test for Antagonism (Data Per Well of a 384-Well Plate):

To a test plate with the substance solutions already added (0.05 μl;100% DMSO, concentration range from 0.8 nM-16.5 nM) were added 4 μl of acAMP-d2/cell suspension (625000 cells/ml). After a 20-minutepreincubation at room temperature (RT), 2 μl of a 3×PGE2 solution (1.5nM, in PBS-IBMX) were added and incubated in the presence of the agonistfor a further 60 mins at RT (volume: ˜6 n1). Next the reaction wasstopped by addition of 2 μl of lysis buffer and incubated for a further20 mins at RT before the actual measurement (volume: ˜8 μl).

2. Detection of Antagonism to the Human Prostaglandin E2 (Subtype EP4)Receptor Signal

2.1 Detection Principle

The binding of PGE₂ to the EP₄ subtype of the human PGE₂ receptorinduces the activation of membrane-located adenylate cyclases and leadsto the formation of cAMP. In the presence of the phosphodiesteraseinhibitor IBMX, the cAMP accumulated owing to this stimulation andreleased by cell lysis is used in a competitive detection method. Inthis test, the cAMP present in the lysate competes with afluorescence-labelled cAMP (cAMP-d2) for binding to an Eucryptate-labelled anti-cAMP antibody.

In the absence of cellular cAMP a maximal signal is produced, which isattributable to the binding of this cAMP-d2 molecule to the antibody.After excitation of the cAMP-d2 molecule at 337 nm, there is afluorescence resonance energy transfer (FRET) to the Eu cryptatemolecules of the anti-cAMP antibody (labelled therewith), followed by along-lasting emission signal at 665 nm (and at 620 nM). Both signals aremeasured in a suitable measurement instrument with a time delay, i.e.after decay of the background fluorescence. Any increase in the low FRETsignal caused by prostaglandin E₂ administration (measured as well ratiochange=emission_(665nm)/emission_(620nm)*10000) indicates the action ofantagonists.

2.2. Detection Method

2.2.1. Test for Antagonism (Data Per Well of a 384-Well Plate):

To a test plate with the substance solutions already added (0.05 μl;100% DMSO, concentration range from 0.8 nM-16.5 uM) were added 4 μl of acAMP-d2/cell suspension (312500 cells/ml). After a 20-minutepreincubation at room temperature (RT), 2 μl of a 3×PGE2 solution (0.3nM, in PBS-IBMX) were added and incubated in the presence of the agonistfor a further 60 mins at RT (volume: ˜6 μl). Next the reaction wasstopped by addition of 2 μl of lysis buffer and incubated for a further20 mins at RT before the actual measurement (volume: ˜8 μl).

3. Detection of Antagonism to the Human Prostaglandin D Receptor Signal

3.1 Detection Principle

The binding of prostaglandin D₂ to the human PGD receptor induces theactivation of membrane-located adenylate cyclases and leads to theformation of cAMP. In the presence of the phosphodiesterase inhibitorIBMX, the cAMP accumulated owing to this stimulation and released bycell lysis is used in a competitive detection method. In this test, thecAMP present in the lysate competes with a fluorescence-labelled cAMP(cAMP-d2) for binding to an Eu cryptate-labelled anti-cAMP antibody.

In the absence of cellular cAMP, a maximal signal is produced, which isattributable to the binding of this cAMP-d2 molecule to the antibody.After excitation of the cAMP-d2 molecule at 337 nm, there is afluorescence resonance energy transfer (FRET) to the Eu cryptatemolecules of the anti-cAMP antibody (labelled therewith), followed by along-lasting emission signal at 665 nm (and at 620 nM). Both signals aremeasured in a suitable measurement instrument with a time delay, i.e.after decay of the background fluorescence. Any increase in the low FRETsignal caused by prostaglandin E2 administration (measured as well ratiochange=emission_(665nm)/emission_(620nm)*10000) indicates the action ofantagonists.

3.2. Detection Method

3.2.1. Test for Antagonism (Data Per Well of a 384-Well Plate):

To a test plate with the substance solutions already added (0.05 μl;100% DMSO, concentration range from 0.8 nM-16.5 nM) were added 4 μl of acAMP-d2/cell suspension (625000 cells/ml). After a 20-minutepreincubation at room temperature (RT), 2 μl of a 3×PGD2 solution (6 nM,in PBS-IBMX) were added and incubated in the presence of the agonist fora further 30 mins at RT (volume: ˜6 μl). Next the reaction was stoppedby addition of 2 μl of lysis buffer and incubated for a further 20 minsat RT before the actual measurement (volume: ˜8 μl).

4. The EP2 Subtype of the PGE2 Receptor and the Pre-Ovulatory CumulusExpansion

4.1. Background:

In the pre-ovulatory antral follicle, the oocyte is surrounded bycumulus cells, which form a dense cell crown around the oocyte. Afterthe LH peak (luteinizing hormone), a series of processes is activated,which results in a marked morphological change in this cell crown ofcumulus cells. During this, the cumulus cells form an extracellularmatrix, which leads to the so-called cumulus expansion (Vanderhyden etal. Dev Biol.; (1990); 140(2): 307-317) This cumulus expansion is animportant component of the ovulatory process and the subsequentpossibility of fertilization.

During the cumulus expansion, prostaglandins and here prostaglandin E₂,synthesis whereof is induced by the LH peak, are of decisive importance.Prostanoid EP2 knockout mice (Hizaki et al., 1999, Proc Natl Acad SciU.S.A; (1999) 96(18):10501-10506) show a markedly decreased cumulusexpansion and severe subfertility, which demonstrates the importance ofthe prostanoid EP2 receptor for this process.

4.2. Cumulus Expansions Test In Vitro

In immature female mice (strain: B6D2F1 from Charles River), at an ageof 14-18 days, the folliculogenesis was induced by a singleadministration (intraperitoneal) of 10 IU of PMSG (pregnant mare serumgonadotropin; Sigma G-4877, Lot 68H0909). 47-50 hours after theinjection, the ovaries were removed and the cumulus-oocyte complexesremoved. At this stage, the cumulus complex is not yet expanded.

The cumulus-oocyte complexes were now incubated for 20-24 hours withprostaglandin E₂ (PGE₂) (0.3 μM), vehicle control (ethanol) or testsubstances. Medium: alpha-MEM medium with 0.1 mM IBMX, pyruvate (0.23mM), glutamine (2 mM), pen/strep 100 IU/ml pen. and 100 μg/m1 strep.),HSA (8 mg/ml) and foetal bovine serum (FBS, 10%). The cumulus expansionwas then established through the subdivision into four stages (afterVanderhyden et al. Dev Biol.; (1990); 140(2):307-317).

4.3 In-Vivo Action on Post-Ovulatory In-Vitro Fertilization:

Substances can exert an influence on fertility by decreasing thefertilizability of oocytes or cumulus-oocyte complexes. In order tostudy such effects, substances can be administered in vivo and subjectedto in vitro fertilization after ovulation of cumulus-oocyte complexeshas taken place. The in-vitro fertilization rate, where no testsubstance is any longer present, allows conclusions as to the in-vivoeffects of the test substances.

Immature female mice (strain: B6D2F1, Charles River, Suelzfeld, age:19-25 days) were kept in Macrolon cages in rooms with controlledillumination (12 hrs darkness: 12 hrs light), fed with a standard dietand provided with drinking water ad libitum.

The mice were primed with PMSG (pregnant mare serum gonadotropin) (10IU/animal i.p.). After 48 hours, a stimulus triggering ovulation wascreated in the animals by one administration of 10 IU/animal i.p. (hCG,human chorionic gonadotropin). The test substances were dissolved inbenzyl benzoate/castor oil (1+4 v/v) and administered in a volume of 0.1ml s.c. 1 hour before hCG (n=5 animals per group). Fourteen hours afterhCG administration, the animals were killed. Ovulated oocytes andcumulus-oocyte complexes were obtained from the bursa ovarii and/oroviduct and subjected to in-vitro fertilization, wherein for thefertilization a sperm count of 40000 sperms/0.5 ml was used for 1 hour.Twenty-four hours after the incubation with the sperms, the number offertilized oocytes is established and the percentage fertilization ratedetermined

The results in Table 4 show that Example 17 according to the inventionhas a dose-dependent influence on the fertilizability of ovulatedcumulus-oocyte complexes.

4.4 In-Vivo Action on Fertility in Non-Human Primates (Cynomolgus):

In order to study the effect of substances on fertility, mating studiescan be performed in monkeys (Jensen et al. Contraception 81; (2010)82(2): 165-171). For this, the test substances are administered tofemale cynomolgus monkeys (Macaca Fascicularis) which are being kept ingroups, then the animals are mated with a male animal. Matings arechecked for by sperm detection in daily vaginal smears. Pregnanciesresulting therefrom are identified by hormone determinations andultrasound examinations. Through the changes in the serum oestradiolconcentrations during the cycle, (rise before the midcycle LH peak), thefertile phase within a cycle of the individual animals can bedetermined. Matings in this fertile period are described as “timedmatings” (matings in the fertile phase). Apart from the absolute numberof pregnancies occurring, the effect on the fertility can also beexpressed as pregnancies per “timed matings”.

To test the action of EP2 receptor antagonists on fertility in monkeys,Examples 17 and 56 according to the invention were administered over 6months, dissolved in 0.5 ml castor oil. Example 17 was administered oncedaily at a dosage of 10 mg/kg (n=10 animals), while Example 56 wasadministered twice daily at a dosage of 10 mg/kg (n=9 animals). Only thevehicle was administered to a control group (n=10 animals). In the firstmonth of the treatment, no male animal was placed with the femaleanimals. After this, female and male animals were kept together over 5months, with detection of pregnancies and cycle monitoring.

Table 5 shows that both substances result in a marked reduction in thenumber of pregnancies occurring. These data for the first time show thestrong contraceptive effect of EP2 receptor antagonists in the primate.Further results of the study show that the substances have no effects onhormone levels and cycle length. This confirms that the substancesproduce a contraceptive effect by non-hormonal mechanisms. Thereversibility of the fertility was demonstrated on some animals afterdiscontinuation of the treatment.

5. Determination of the Pharmacokinetic Parameters after IntravenousAdministration

5.1. Intravenous Administration:

For this, the substances were administered in dissolved form, compatiblesolubilizers such as PEG400 and/or ethanol being used in tolerablequantity. The substances were administered at a dosage of 0.1-1 mg/kg.The administration was effected in the female rat as a bolus injection.Here, at various times after bolus injection ca. 100-150 μl bloodsamples were withdrawn from the jugular vein via a catheter. The bloodsamples were treated with lithium-heparin as anticoagulant and storedrefrigerated until further work-up. After centrifugation of the samplesfor 15 mins at 3000 rpm, an aliquot of 100 μl was withdrawn from thesupernatant (plasma) and precipitated by addition of 400 μl of coldacetonitrile or methanol (absolute). The precipitated samples werefrozen overnight at −20° C., then centrifuged once again for 15 mins at3000 rpm, before 150 μl of the clear supernatant was withdrawn for theconcentration determination. The analysis was performed with an Agilent1200 HPLC system with attached LCMS/MS detection.

5.2 Calculation of the PK Parameters

The calculation was performed by means of the PK calculation softwareWinNonLin®, where t_(1/2) means half-life within a specified interval(here: terminal t_(1/2), in hrs).

TABLE 1 Examples for the biological activity of the compounds accordingto the invention on the hEP2 receptor (IC₅₀ measured by cAMP antagonismtest), selectivity towards hDP & hEP₄ (IC₅₀ measured by cAMP antagonismtest): x: 1-10, xx: 10-100, xxx >100: Antagonism hEP2 SelectivitySelectivity Example IC₅₀ [M] hEP2/hDP hEP2/hEP4 1 1.03E−07 xxx xxx 22.17E−08 xxx xxx 3 4.91E−09 xxx xxx 4 6.81E−08 xxx xxx 5 5.11E−09 xxxxxx 6 3.13E−07 xx xx 7 2.58E−08 xxx xxx 8 9.37E−09 xxx xxx 9 1.72E−08xxx xxx 10 8.67E−09 xxx xxx 11 8.14E−09 xxx xxx 12 2.03E−08 xxx xxx 133.59E−08 xxx xxx 14 3.67E−09 xxx xxx 15 4.17E−09 xxx xxx 16 5.85E−09 xxxxxx 17 3.44E−09 xxx xxx 18 7.66E−09 xxx xxx 19 8.57E−09 xxx xxx 207.33E−09 xxx xxx 21 3.58E−08 xxx xxx 22 3.03E−08 xxx xxx 23 1.61E−08 xxxxxx 24 6.01E−08 xxx xxx 25 2.52E−08 xxx xxx 26 2.42E−08 xxx xxx 271.93E−08 xxx xxx 28 3.39E−08 xxx xxx 29 9.31E−09 xxx xxx 30 6.43E−08 xxxxxx 31 3.08E−09 xxx xxx 32 1.04E−08 xxx xxx 33 3.42E−08 xxx xxx 341.34E−07 xxx xxx 35 6.92E−08 xxx xxx 36 6.16E−08 xxx xxx 37 1.04E−07 xxxxxx 38 2.81E−08 xxx xxx 39 1.13E−07 xxx xxx 40 1.15E−08 xxx xxx 415.62E−09 xxx xxx 42 4.75E−09 xxx xxx 43 4.82E−09 xxx xxx 44 3.85E−09 xxxxxx 45 5.51E−09 xxx xxx 46 4.91E−09 xxx xxx 47 5.61E−09 xxx xxx 485.59E−09 xxx xxx 49 6.44E−09 xxx xxx 50 3.18E−09 xxx xxx 51   6E−08 xxxxxx 52  8.3E−07 xx xx 53 4.42E−08 xxx xxx 54 4.74E−09 xxx xxx 559.67E−09 xxx xxx 56 1.31E−08 xxx xxx 57 5.29E−09 xxx xxx 58 1.08E−06 xxxx 59 7.58E−07 xx xx 60 1.75E−07 xx xx 61  1.5E−06 xx xx 62 6.74E−07 xxxx 63 1.44E−06 xx xx 64 4.13E−06 x x 65 2.79E−06 x x 66 3.21E−07 xx xx67 4.05E−07 xx xx 68 1.77E−08 xxx xxx 69  2.9E−08 xxx 70  4.9E−08 xxx 718.29E−08 xxx xxx 72  1.2E−07 xxx xxx 73 7.78E−08 xxx xxx 74 9.54E−08 xxxxxx 75  6.7E−08 xxx xxx 76 1.79E−07 xx xx 77 5.39E−08 xxx xxx 783.17E−08 xxx xxx 79 1.25E−07 xxx xxx 80 8.59E−08 xxx xxx 81 5.13E−07 xxxx 82 2.18E−07 xx xx 83 3.26E−08 xxx xxx 84 1.92E−08 xxx xxx 85 3.55E−08xxx xxx 86 1.54E−08 xxx xxx 87  2.4E−08 xxx xxx 88 1.62E−08 xxx xxx 89 9.4E−09 xxx xxx 90 1.48E−08 xxx xxx 91 2.03E−08 xxx xxx 92 1.27E−08 xxxxxx 93 1.15E−08 xxx xxx 94 1.28E−08 xxx xxx 95 6.18E−09 xxx xxx 969.42E−09 xxx xxx 97 1.27E−08 xxx xxx 98 7.07E−09 xxx xxx 99 1.04E−08 xxxxxx 100 6.21E−09 xxx xxx 101 6.58E−09 xxx xxx 102  4.1E−07 xx xx 1035.95E−07 xx xx 104 5.13E−07 xx xx 105 2.85E−07 xx xx 106  1.5E−07 xxxxxx 107 1.14E−08 xxx xxx 108 6.46E−09 xxx xxx 109 9.53E−09 xxx xxx 110 4.4E−09 xxx xxx 111 1.37E−08 xxx xxx 112 1.19E−08 xxx xxx 113 1.39E−08xxx xxx 114 6.08E−09 xxx xxx 115 9.05E−09 xxx xxx 116 5.52E−09 xxx xxx117 1.78E−08 xxx xxx 118 8.17E−09 xxx 119 1.32E−08 xxx 120 1.55E−08 xxx121 1.55E−08 xxx xxx 122 2.86E−08 xxx xxx 123 8.92E−09 xxx xxx 1247.99E−09 xxx xxx 125 3.66E−09 xxx xxx 126 2.12E−08 xxx xxx 127 5.56E−08xxx xxx 128 4.71E−07 xx xx 129 3.09E−07 xx xx 130 2.41E−07 xx xx 1312.28E−07 xx xx 132 1.09E−07 xxx xxx 133 4.19E−08 xxx xxx 134 5.65E−08xxx xxx 135 1.95E−08 xxx xxx 136 6.59E−09 xxx xxx 137 7.65E−09 xxx xxx138  1.6E−07 xxx xxx 139 4.19E−07 xx xx 140 5.53E−08 xxx xxx 1411.43E−07 xxx xxx 142 7.13E−07 xx xx 143 3.68E−08 xxx xxx 144 5.08E−08xxx xxx 145 1.88E−08 xxx xxx 146 5.26E−08 xxx xxx 147 5.74E−08 xxx xxx148 2.74E−08 xxx xxx 149 2.96E−08 xxx xxx 150 1.28E−08 xxx xxx 1514.85E−08 xxx xxx 152 3.33E−08 xxx xxx 153 6.08E−08 xxx xxx 154 8.08E−08xxx xxx 155 2.94E−08 xxx xxx 156 1.84E−07 xx xx 157 1.36E−08 xxx xxx 1586.21E−09 xxx xxx 159 6.24E−09 xxx xxx 160 8.29E−08 xxx xxx 161 9.82E−08xxx xxx 162 9.33E−09 xxx xxx 163  6.8E−09 xxx xxx 164 1.09E−08 xxx xxx165 3.34E−08 xxx xxx 166 2.87E−09 xxx xxx 167 1.35E−08 xxx xxx 1682.93E−08 xxx xxx 169 2.77E−08 xxx xxx 170 4.25E−09 xxx xxx 171 3.88E−09xxx xxx 172 3.16E−09 xxx xxx 173 2.71E−09 xxx xxx 174 6.58E−09 xxx xxx175 8.05E−09 xxx xxx 176 7.77E−09 xxx xxx 177 1.18E−07 xxx xxx 1786.83E−08 xxx xxx 179 2.61E−06 x x 180 1.73E−08 xxx xxx 181 3.52E−08 xxxxxx 182 6.42E−08 xxx xxx 183 4.66E−08 xxx xxx 184 7.68E−08 xxx xxx 1852.48E−08 xxx xxx 186 5.19E−08 xxx xxx 187 2.35E−08 xxx xxx 188 1.49E−07xxx xxx 189 3.36E−08 xxx xxx 190 2.72E−07 xx xx 191 4.71E−08 xxx xxx 1922.06E−07 xx xx 193 1.45E−07 xxx xxx 194 4.09E−08 xxx xxx 195 2.27E−07 xxxx 196 5.08E−08 xxx xxx 197 6.32E−08 xxx xxx 198 1.53E−07 xxx xxx 1999.71E−08 xxx xxx 200 1.51E−08 xxx xxx 201 2.49E−08 xxx xxx 202 5.06E−09xxx xxx 203 8.57E−08 xxx xxx 204   1E−08 xxx xxx 205 4.33E−08 xxx xxx206 4.13E−08 xxx xxx 207 3.03E−08 xxx xxx 208 8.06E−08 xxx xxx 2092.51E−08 xxx xxx 210 1.95E−08 xxx xxx 211 5.01E−08 xxx xxx 212 1.06E−07xxx xxx 213 8.24E−08 xxx xxx 214 6.49E−08 xxx xxx 215  3.9E−08 xxx xxx216 8.61E−08 xxx xxx 217 1.14E−07 xxx xxx 218 1.28E−07 xxx xxx 2192.73E−07 xx xx 220 1.47E−07 xxx xxx 221 2.35E−07 xx xx 222 4.09E−08 xxxxxx 223   2E−08 xxx xxx 224 5.62E−09 xxx xxx 225 1.43E−08 xxx xxx 2261.19E−08 xxx xxx 227 9.89E−09 xxx xxx 228 8.09E−09 xxx xxx 229 1.02E−08xxx xxx 230 1.37E−08 xxx xxx 231 1.32E−08 xxx xxx 232 3.83E−08 xxx xxx233 3.97E−08 xxx xxx 234 4.77E−08 xxx xxx 235 1.67E−08 xxx xxx 2365.75E−08 xxx xxx 237  3.1E−08 xxx xxx 238 3.24E−08 xxx xxx 239  2.7E−08xxx xxx 240 2.51E−08 xxx xxx 241 9.03E−09 xxx xxx 242 3.05E−07 xx xx 2433.35E−07 xx xx 244 4.42E−08 xxx xxx 245 7.79E−09 xxx xxx 246 9.23E−09xxx xxx 247 1.26E−08 xxx xxx 248 1.47E−08 xxx xxx 249 1.12E−08 xxx xxx250 3.06E−08 xxx xxx 251 3.81E−06 x x 252 2.95E−07 xx xx 253 1.68E−07 xxxx 254 5.52E−08 xxx xxx 255 8.35E−08 xxx xxx 256 1.07E−07 xxx 2571.02E−07 xxx xxx 258 1.09E−07 xxx xxx 259 2.56E−08 xxx xxx 260 8.02E−09xxx xxx 261  8.1E−08 xxx xxx 262 3.34E−08 xxx xxx 263 1.81E−07 xx xx 2641.37E−08 xxx xxx 265 3.15E−08 xxx xxx 266 1.89E−08 xxx xxx 267 4.55E−08xxx xxx 268 2.29E−08 xxx xxx 269 7.54E−09 xxx xxx 270 5.31E−08 xxx xxx271 3.35E−08 xxx xxx 272 2.37E−08 xxx xxx 273 1.85E−08 xxx xxx 2744.46E−08 xxx xxx 275 3.45E−08 xxx xxx 276 2.26E−07 xx xx 277 4.79E−08xxx xxx 278 1.04E−07 xxx xxx 279 5.74E−08 xxx xxx 280 3.07E−08 xxx xxx281  2.3E−08 xxx xxx 282 2.01E−08 xxx xxx 283 6.55E−08 xxx xxx 2845.64E−08 xxx xxx 285   1E−07 xxx xxx 286   1E−07 xxx xxx 287 1.05E−06 xxxx 288   4E−08 xxx xxx 289 5.16E−08 xxx xxx 290 4.26E−08 xxx xxx 2915.94E−09 xxx xxx 292   2E−08 xxx xxx 293 2.83E−08 xxx xxx 294 1.32E−08xxx xxx 295 7.08E−08 xxx xxx 296 2.97E−08 xxx xxx 297  4.6E−07 xx xx 2983.45E−07 xx xx 299 5.41E−07 xx xx 300 7.98E−08 xxx xxx 301 2.45E−08 xxxxxx 302 1.31E−07 xxx xxx 303 1.39E−08 xxx xxx 304 9.98E−08 xxx xxx 3053.01E−07 xx xx 306 7.66E−08 xxx xxx 307 3.06E−08 xxx xxx 308 2.22E−08xxx xxx 309  6.6E−08 xxx xxx 310 8.06E−07 xx xx 311 8.41E−08 xxx xxx 3121.58E−07 xxx xxx 313 8.94E−08 xxx xxx 314 2.78E−08 xxx xxx 315  4.3E−08xxx xxx 316  7.9E−08 xxx xxx 317 1.81E−07 xx xx 318 2.63E−08 xxx xxx 3193.15E−07 xx xx 320 1.56E−08 xxx xxx 321 1.01E−07 xxx xxx 322 7.62E−08xxx xxx 323 1.28E−07 xxx xxx 324  4.6E−07 xx xx 325 3.21E−07 xx xx 3264.85E−07 xx xx 327 1.21E−06 xx xx 328 2.56E−07 xx xx 329 2.32E−07 xx xx330 9.53E−09 xxx xxx 331 9.47E−09 xxx xxx 332 5.47E−09 xxx xxx 3336.42E−09 xxx xxx 334 7.42E−08 xxx xxx 335 5.09E−09 xxx xxx 336 5.59E−09xxx xxx 337 1.81E−08 xxx xxx 338  2.8E−08 xxx xxx 339 7.15E−09 xxx xxx340 1.99E−08 xxx xxx 341 5.53E−08 xxx xxx 342 1.03E−07 xxx xxx 3434.24E−08 xxx xxx 344 1.03E−08 xxx xxx 345 6.26E−09 xxx xxx 346 1.49E−08xxx xxx 347 7.88E−09 xxx xxx 348 8.88E−09 xxx xxx 349 4.82E−09 xxx xxx350 8.41E−09 xxx xxx 351 6.84E−09 xxx xxx 352 2.17E−08 xxx xxx 3535.02E−08 xxx xxx 354 5.87E−09 xxx xxx 355 5.39E−09 xxx xxx 356 6.36E−08xxx xxx 357 7.36E−09 xxx xxx 358 8.01E−09 xxx xxx 359 6.99E−09 xxx xxx360 6.27E−09 xxx xxx 361 5.11E−09 xxx xxx 362 1.51E−08 xxx xxx 3635.48E−09 xxx xxx 364 6.61E−09 xxx xxx 365  5.3E−09 xxx xxx 366 1.89E−08xxx xxx 367 5.84E−09 xxx xxx 368  1.2E−08 xxx xxx 369 5.66E−09 xxx xxx370 3.07E−09 xxx xxx 371 6.11E−09 xxx xxx 372 7.29E−09 xxx xxx 3734.07E−08 xxx xxx 374 6.58E−09 xxx xxx 375  5.8E−09 xxx xxx 376 3.59E−09xxx xxx 377 2.73E−08 xxx xxx 378 7.77E−09 xxx xxx 379 6.26E−08 xxx xxx380 5.35E−09 xxx xxx 381 5.84E−09 xxx xxx 382 1.94E−08 xxx xxx 3835.78E−09 xxx xxx 384 3.95E−09 xxx xxx 385 1.31E−08 xxx xxx 386 2.57E−08xxx xxx 387 1.32E−08 xxx xxx 388 2.05E−08 xxx xxx 389 4.51E−09 xxx xxx390 3.14E−09 xxx xxx 391 6.07E−09 xxx xxx 392 2.18E−08 xxx xxx 393  5E−08 xxx xxx 394  5.7E−09 xxx xxx 395 3.04E−08 xxx xxx 396  1.8E−08xxx xxx 397 1.25E−08 xxx xxx 398 1.82E−08 xxx xxx 399 5.93E−07 xx xx 4005.61E−08 xxx xxx 401 1.55E−07 xxx xxx 402 7.77E−08 xxx xxx 403 9.59E−09xxx xxx 404 2.02E−08 xxx xxx 405 2.14E−06 x x 406 8.19E−09 xxx xxx 4071.16E−08 xxx xxx 408 2.35E−08 xxx xxx 409 3.18E−08 xxx xxx 410 9.04E−08xxx xxx 411 1.65E−08 xxx xxx 412 6.35E−08 xxx xxx 413 3.78E−08 xxx xxx414 2.23E−07 xx xx 415 2.13E−08 xxx xxx 416 1.07E−08 xxx xxx 4179.75E−09 xxx xxx 418 1.58E−08 xxx xxx 419 1.09E−08 xxx xxx

TABLE 2 Reduction in the cumulus expansion in percent with use of 0.3 μMPGE2 for stimulation, reference 1: example 62 from DE102009049662A1Example % reduction at 1 μM % reduction at 0.5 μm Reference 1* 79%(*reduction at 10 μM) Example 5 59 56 Example 17 76 71 Example 42 79 48Example 117 54 30 Example 283 26 25 Example 291 73 76 Example 303 47 38Example 345 36 18

TABLE 3 Terminal half-life (t_(1/2)) after intravenous administration inthe female rat, reference 1: example 62 from DE102009049662A1 Examplet_(1/2) [hr] Reference 1 0.4 Example 17 2.5 Example 42 3.2 Example 1172.0 Example 283 5.8

TABLE 4 Reduction in in-vitro fertilization rate after in-vivoadministration of the test substance: % fertiliza- % fertiliza- %fertiliza- % fertiliza- tion with tion with tion with tion with Examplevehicle 1 mg/kg 5 mg/kg 10 mg/kg Example 17 30 ± 9 20 ± 10 9 ± 1 8 ± 4

TABLE 5 Reduction in the pregnancy rates in the non-human primate(Cynomolgus) Animals Number of Preg- % Pregnancies/ Group per group“timed matings”* nancies “timed mating” Control 10 21 8 38 Example 17 1025 3 6 Example 56 9 34 2 12 *Detection of vaginal sperms in the fertilephase of the cycle6. Effect of a Single Administration of EP2 Receptor Antagonists and COXInhibitors Alone or in Combination on the Fertility of the Rat

The rat is a particularly suitable animal model for demonstrating theeffect of substances on fertility, since the cycle can be observedeasily by vaginal swabs and mating reliably leads to a high number ofoffspring.

In the experiments below, female Han Wistar rats having a weight of200-270 g were used. The animals were kept in Makrolon cages in roomswith controlled lighting (12 hours of darkness; 12 hours of light), fedwith a standard diet and provided with water ad libitum.

EP2 receptor antagonists were dissolved in benzyl benzoate/castor oil(1+4 v/v), and the dose was administered in a volume of 1 ml/kg of bodyweight s.c. Optionally, EP2 receptor antagonists were also administeredorally in the same vehicle as the COX inhibitors (see below). Here, theoral administrations were divided to three points in time (12.30, 16.00and 17.00 hours) (see Table 6.3).

The COX inhibitors were suspended in a carrier liquid (85 mg of Myrj®53polyoxyl(50)stearate; CAS No. 9004-99-3) in 100 ml of 0.9% w/v NaClsolution), and the dose corresponding to the treatment group wasadministered in a volume of 2 ml/kg of body weight.

Prior to the start of the experiment, two cycles were observed usingvaginal swabs. Only animals having a regular 4-day cycle were used inthe experiment. The animals were randomized to the treatment groups.

The animals were treated once in the proestrus, the day in the cyclewhen the LH peak occurs in the evening, with the test substances eitheralone or in combination. On the evening of the proestrus, the femaleanimals mated with a male rat. Successive mating was confirmed bydetection of vaginal sperms in the vaginal swab the next morning. Theeffect on fertility was determined 9-15 days after mating by the numberof implantation sites of the animals. The group size was n=6 per group.

As can be seen from Tables 6.1-6.6, in these experiments piroxicam,indomethacin and meloxicam in combination with various EP2 receptorantagonists had a strong antifertility effect. In particular, it shouldbe noted that the individual administrations showed no or only a weakeffect, whereas the combination showed a markedly increasedcontraceptive efficacy.

TABLE 6.1 Effect of a single administration of the EP2 receptorantagonist E16: N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide (Example 17) or piroxicam alone or incombination on the fertility of the female rat. Absolute Time ofimplantations Implantations treatment number of per animal Treatmentgroup (o'clock) 6 animals (mean ± SD) Vehicle 7:00 74 12.3 ± 0.8  E16 4mg/animal 7:00 54 9.0 ± 3.4 Piroxicam 2 mg/animal 7:00 81 13.5 ± 1.0 E16 4 mg/animal + 7:00 22 3.7 ± 4.3 Piroxicam 2 mg/animal E16 4mg/animal 13:00   49* 8.2 ± 3.1 Piroxicam 2 mg/animal 13:00  68 11.3 ±1.6  E16 4 mg/animal + 13:00   8* 1.4 ± 1.1 Piroxicam 2 mg/animal *Dataof n = 5 animals since one animal did not mate (no sperms detected inthe vaginal swab)

TABLE 6.2 Effect of a single administration of the EP2 receptorantagonist E161: N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide (Example 345) or piroxicam alone or incombination on the fertility of the female rat. Absolute Time ofimplantations Implantations treatment number of per animal Treatmentgroup (o'clock) 6 animals (mean ± SD) Vehicle 18:00 77 12.8 ± 2.2 E161 2mg/animal 18:00 55  9.0 ± 3.4 Piroxicam 2 mg/animal 18:00  53* 10.6 ±1.5 E161 2 mg/animal + 18:00 24  4.0 ± 2.1 Piroxicam 2 mg/animal *Dataof n = 5 animals since one animal did not mate (no sperms detected inthe vaginal swab)

TABLE 6.3 Effect of an oral administration of EP2 receptor antagonistE16: N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide (Example 17) or E161: N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide (Example 345) or piroxicam aloneor in combination on the fertility of the female rat. Absolute Time ofimplantations Implantations treatment number of per animal Treatmentgroup (o'clock)# 6 animals (mean ± SD) Vehicle 12:30; 16:00 73 12.3 ±1.2 and 17:00 Piroxicam 2 mg/animal 12:30 71 11.8 ± 3.7 E16 2 mg/animal16:00 63 10.5 ± 1.5 and 17:00 E161 2 mg/animal 16:00 69 11.5 ± 3.1 and17:00 E16 2 mg/animal + 12:30; 16:00 21  3.5 ± 2.9 Piroxicam 2 mg/animaland 17:00 E161 2 mg/animal + 12:30; 16:00 32  5.3 ± 4.1 Piroxicam 2mg/animal and 17:00 #Dosage of the EP2 receptor antagonists was dividedto two points in time after administration of the COX inhibitor

TABLE 6.4 Effect of a single administration of the EP2 receptorantagonist E16: N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide (Example 17) or meloxicam in various dosagesalone or in combination on the fertility of the female rat. AbsoluteTime of implantations Implantations treatment number of per animalTreatment group (o'clock)# 6 animals (mean ± SD) Vehicle 17:00  31***10.3 ± 0.6  Meloxicam 0.25 mg/animal 17:00 32* 6.4 ± 5.9 Meloxicam 0.5mg/animal 17:00 70  11.7 ± 6.4  Meloxicam 1 mg/animal 17:00 66   11 ±5.5 Meloxicam 2 mg/animal 17:00 54* 10.8 ± 4.4  E16 4 mg/animal 17:00 22** 5.5 ± 5.4 E16 4 mg/animal + 17:00 31* 6.2 ± 6.3 Meloxicam 0.25mg/animal E16 4 mg/animal + 17:00  15*** 5.0 ± 1.7 Meloxicam 0.5mg/animal E16 4 mg/animal + 17:00 11* 2.2 ± 3.3 Meloxicam 1 mg/animalE16 4 mg/animal + 17:00  7** 1.8 ± 2.4 Meloxicam 2 mg/animal *Data of n= 5 animals since one animal did not mate (no sperms detected in thevaginal swab) **Data of n = 4 animals since two animals did not mate (nosperms detected in the vaginal swab) ***Data of n = 3 animals sincethree animals did not mate (no sperms detected in the vaginal swab)

TABLE 6.5 Effect of a single dose-dependent administration of the EP2receptor antagonist E16: N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide (Example 17) or meloxicam alone or incombination on the fertility of the female rat. Absolute Time ofimplantations Implantations treatment number of per animal Treatmentgroup (o'clock)# 6 animals (mean ± SD) Vehicle 17:00  61* 12.2 ± 1.9 E16 0.25 mg/animal 17:00 78  13 ± 2.3 E16 0.5 mg/animal 17:00 60  10 ±2.8 E16 1 mg/animal 17:00 42  7 ± 5.4 E16 2 mg/animal 17:00  30** 7.5 ±1.7 E16 4 mg/animal 17:00 32 5.3 ± 4.5 Meloxicam 2 mg/animal 17:00  63*12.6 ± 3.4  E16 0.25 mg/animal + 17:00 52 8.7 ± 2.5 Meloxicam 2mg/animal E16 0.5 mg/animal + 17:00 36 6.0 ± 4.3 Meloxicam 2 mg/animalE16 1 mg/animal + 17:00 35 5.8 ± 3.4 Meloxicam 2 mg/animal E16 2mg/animal + 17:00 19 3.2 ± 2.8 Meloxicam 2 mg/animal E16 4 mg/animal +17:00   11*** 3.7 ± 4.7 Meloxicam 2 mg/animal *Data of n = 5 animalssince one animal did not mate (no sperms detected in the vaginal swab)**Data of n = 4 animals since two animals did not mate (no spermsdetected in the vaginal swab) ***Data of n = 3 animals since threeanimals did not mate (no sperms detected in the vaginal swab)

TABLE 6.6 Effect of a single dose-dependent administration of the EP2receptor antagonist E16: N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide (Example 17) or indomethacin alone or incombination on the fertility of the female rat. Absolute Time ofimplantations Implantations treatment number of per animal Treatmentgroup (o'clock)# 6 animals (mean ± SD) Vehicle 16:00 67 11.2 ± 2.6  E161 mg/animal 16:00 62 10.3 ± 2.5  E16 2 mg/animal 16:00 71 11.8 ± 2.1 E16 4 mg/animal 16:00 50 8.3 ± 3.4 E16 8 mg/animal 16:00  43* 8.6 ± 2.8Indomethacin 1 mg/animal 16:00 67 11.2 ± 2.9  E16 1 mg/animal + 16:00 589.7 ± 1.9 Indomethacin 1 mg/animal E16 2 mg/animal + 16:00 38 6.3 ± 3.7Indomethacin 1 mg/animal E16 4 mg/animal + 16:00 27 4.5 ± 1.6Indomethacin 1 mg/animal E16 8 mg/animal + 16:00 26 4.3 ± 1.9Indomethacin 1 mg/animal *Data of n = 5 animals since one animal did notmate (no sperms detected in the vaginal swab)7. In-Vivo Effect on Postovulatory In-Vitro Fertilization in the Mouse

Substances can influence fertility by lowering fertilizability ofoocytes or cumulus-oocyte complexes. To examine such effects, substancescan be administered in vivo and, after ovulation of cumulus-oocytecomplexes, the latter are subjected to in-vitro fertilization. Thein-vitro fertilization rate in the absence of test substance allowsconclusions to be drawn on the in-vivo effects of the test substances.

Immature female mice (strain: B6D2F1, Charles River, Suelzfeld, age:19-25 days) were kept in Makrolon cages in rooms with controlledlighting (12 hours of darkness: 12 hours of light), fed with a standarddiet and provided with water ad libitum.

The mice were primed with PMSG (Pregnant Mare Serum Gonadotropin) (10IU/animal i.p.). After 48 hours, by administration of 10 IU/animal i.p.,an ovulation-triggering stimulus (hCG, human Chorion Gonadotropin) wasgenerated in the animals. EP2 receptor antagonists were dissolved inbenzyl benzoate/castor oil (1+4 v/v) and administered in a volume of 0.1ml s.c. 1 hour prior to hCG (n=5 animals per group). The COX inhibitorwas suspended in a carrier liquid (85 mg of Myrj®53polyoxyl(50)stearate; CAS No. 9004-99-3) in 100 ml of 0.9% w/v NaClsolution), and the appropriate dose was administered in a volume of 2ml/kg of body weight orally 1 hour prior to hCG. Fourteen hours afteradministration of hCG, the animals were sacrificed. Ovulated oocytes andcumulus-oocyte complexes were obtained from the ovarii bursa and/or theoviduct and subjected to in-vitro fertilization, with a sperm number of40 000 sperms/0.5 ml for 1 hour being used for fertilization.Twenty-four hours after incubation with the sperms, the number offertilized oocytes and the number of 2-cell embryos per animal weredetermined.

TABLE 7.1 The results in this table show that the EP2 receptorantagonist according to the invention E126:4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide (Example 291) has a dose-dependent effect on the number of 2-cell embryos per animal. 2-Cellembryos per animal Treatment group (mean ± SD) Vehicle* 36.3 ± 9.5Piroxicam 0.1 mg/animal 10.8 ± 3.8 E126 0.1 mg/animal 30.8 ± 7.3Piroxicam 0.1 mg/animal +  6.2 ± 4.5 E126 0.1 mg/animal E126 0.5mg/animal 12.6 ± 3.6 Piroxicam 0.1 mg/animal +  3.3 ± 2.1 E126 0.5mg/animal* *Data of n = 4 animals since there was no follicle maturation

Preparation Example 1 Combination tablets comprising 60 mg of piroxicamand 600 mg ofN-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide(E16)

In a fluidized-bed granulator, 1667 g of E16, 167 g of piroxicam, 444 gof microcrystalline cellulose and 125 g of croscarmellose sodium areinitially charged. This powder mixture is granulated using a granulationliquid consisting of 75 g of hydroxypropylmethylcellulose 5 cP, 2.5 g ofsodium lauryl sulphate and 1800 g of water. The granules are dried inthe fluidized-bed granulator and then sieved and subsequently mixed with20 g of magnesium stearate for 5 minutes. The powder mixture is thencompressed on a rotary tablet press to oval tablets having a mass of 900mg, a length of 18 mm and a width of 8 mm. The tablets are then coatedwith a dispersion of 55.6 g of ready-to-use film powder and 315 g ofwater. The ready-to-use film powder consists of 50.56% hypromellose 5cP, 10.12% Macrogol 3350, 10.12% talc, 23.20% titanium dioxide and 6.00%yellow iron oxide.

Combination tablets comprising other EP2 receptor antagonists accordingto the invention and COX inhibitors can be prepared analogously. Foralternative doses, the ratios can be adapted appropriately.

Alternatively, it is posisble to formulate the EP2 receptor antagonistand COX inhibitor separately in separate tablets.

Preparation Example 2 Kit comprising 2 combination tablets comprising 60mg of piroxicam and 600 mg ofN-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide(E16)

A folded box is manufactured which contains 3×2 combination tabletsaccording to Preparation Example 1 and can thus be used for threeexpected sexual intercourses. The composition of the combination tabletsis identical. The folded box furthermore contains a package insert whichdescribes that the woman has to take one tablet orally 6 to 12 hoursbefore sexual intercourse and a further tablet within 24 hours aftersexual intercourse. Furthermore, the package insert indicates thatintake of the second tablet can be dispensed with if there has been nosexual intercourse. If there has been no sexual intercourse after twoadministrations, the two tablets not used because of this may be usedfor a further administration.

The invention claimed is:
 1. A pharmaceutical composition comprising (a)at least one EP2 receptor antagonist according to formula (I)

wherein R¹ is H, C₁-C₂ alkyl or C₁-C₂ alkyloxy; R² is H or methyl;subject to the proviso that one of R¹ or R² equals H; X is —(CH₂)_(l)—,—(CH₂)_(k)—O—, —CH₂—S—, CH₂—S(O)₂—, —CH(CH₃)—, —CH(CH₃)—O— or—C(CH₃)₂—O—, wherein k is 1 or 2 and l is 0, 1 or 2; R⁴ is H, C₁-C₄alkyl, C₃-C₄ cycloalkyl or CH₂-C₃-C₄ cycloalkyl and in the case that Xis —(CH₂)_(l)— where is 0 or 1, or —CH(CH₃)—; R⁴ additionally is a4-6-membered heterocyclyl residue; and in the case that X is —(CH₂)_(l)—or —CH(CH₃)—; R⁴ additionally means CN; m is 1 or 2; n is 1 or 2; Ar isa 6-10-membered aryl or 5-10-membered hetaryl residue, R³ is halogen,CN, SF₅, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₄-C₆ heterocyclyl, O—C₁-C₄alkyl, O—C₃-C₆ cycloalkyl, O—C₄-C₆ heterocyclyl, S—C₁-C₄ alkyl,S(O)₂—C₁-C₄ alkyl, Ar′, O—Ar′, C(CH₃)₂—CN or C(CH₃)₂—OH; and Ar′ is anoptionally singly or doubly substituted 6-membered aryl or 5-6-memberedheteroaryl residue; wherein the substituents are selected from F, Cl,CN, C₁-C₄ alkyl, O—C₁-C₄ alkyl, C(CH₃)₂—CN, C(CH₃)₂—OH and C(O)NH₂;wherein C₁-C₂ alkyl or C₁-C₄ alkyl is optionally singly or multiplysubstituted with fluorine; and at least one COX inhibitor selected froma group consisting of: C1 indomethacin; C2 diclofenac; C4 naproxen; C5ibuprofen; C6 meloxicam; C7 piroxicam; C8 nimesulide; C9 ketoprofen; C10tenoxicam; C11 mefanemic acid; C12 ketoralac; C13 celecoxib(4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulphonamide);C14parecoxib(N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulphonylpropionamide);C15 rofecoxib (4-(4-mesylphenyl)-3-phenylfuran-2(5H)-one); C16valdecoxib (4-[5-methyl-3-phenyl-4-isoxazoyl)benzenesulphonamide); andC17 etoricoxib for on-demand contraception.
 2. A pharmaceuticalcomposition comprising (a) at least one EP2 receptor antagonistaccording to formula (Ia)

wherein R¹, R² is H or methyl; subject to the proviso that one of R¹ orR² equals H; X is —(CH₂)_(l)— or —(CH₂)_(k)—O—; k is 1 or 2; l is 0, 1or 2; R⁴ is H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl or CH₂—C₃-C₄ cycloalkyl; mis 1 or 2; n is 1 or 2; Ar is a 6-10-membered aryl or 5-10-memberedhetaryl residue, R³ is a halogen, CN, SF₅, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₄-C₆ heterocyclyl, O—C₁-C₄ alkyl, O—C₃-C₆ cycloalkyl,O—C₄-C₆ heterocyclyl, S—C₁-C₄ alkyl, S(O)₂—C₁-C₄ alkyl, Ar′, O—Ar′,C(CH₃)₂—CN or C(CH₃)₂—OH; and Ar′ is an optionally singly or doublysubstituted 6-membered aryl or 5-6-membered heteroaryl residue; whereinthe substituents are selected from F, Cl, CN, C₁-C₄ alkyl, O—C₁-C₄alkyl, C(CH₃)₂—CN, C(CH₃)₂—OH and C(O)NH₂; wherein C₁-C₂ alkyl or C₁-C₄alkyl is optionally singly or multiply substituted with fluorine, and anisomer, diastereomer, enantiomer, salt or cyclodextrin clathratesthereof and (b) at least one COX inhibitor selected from the listconsisting essentially of: C1 indomethacin; C2 diclofenac; C4 naproxen;C5 ibuprofen; C6 meloxicam; C7 piroxicam; C8 nimesulide; C9 ketoprofen;C10 tenoxicam; C11 mefanemic acid; C12 ketoralac; C13 celecoxib(4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulphonamide);C14 parecoxib(N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulphonylpropionamide); C15rofecoxib (4-(4-mesylphenyl)-3-phenylfuran-2(5H)-one); C16 valdecoxib(4-[5-methyl-3-phenyl-4-isoxazoyl)benzenesulphonamide); and C17etoricoxib as active compounds and at least one pharmaceuticallyacceptable carrier.
 3. The pharmaceutical composition of claim 2,wherein R¹ is a methyl group; R² is H; X is —(CH₂)_(l)— or—(CH₂)_(k)—O—; k is 1; l is 0 or 1; R⁴ is C₁-C₄ alkyl, C₃-C₄ cycloalkylor CH₂—C₃-C₄ cycloalkyl; m, n is 1; and Ar is a phenyl residue; or andisomer_(s), diastereomer_(s), enantiomer_(s) salts or a cyclodextrinclathrate thereof and R³ and Ar′ have the meanings stated in claim
 2. 4.The pharmaceutical composition of claim 2, wherein R¹ is a methyl group;R² is H; X is —(CH₂)_(l)— or —(CH₂)_(k)—O—; k is 1; l is 0 or 1; R⁴ isC₁-C₄ alkyl, C₃-C₄ cycloalkyl or CH₂—C₃-C₄ cycloalkyl; m, n is 2; and Aris a phenyl residue; or diastereomer, an enantiomer, and salt or acyclodextrin clathrate thereof and R³ and Ar′ have the meanings statedin claim
 2. 5. The pharmaceutical composition according to claim 3 or 4,wherein the EP2 receptor antagonist is selected from the groupconsisting of: E12-{[1-(4-cyano-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E22-{[1-(4-tert-butoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E32-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E4N-(2-methoxyethyl)-4-methyl-2-{[1-(4-morpholinobenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E52-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E62-{[1-(2-fluoro-4-mesylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E72-{[1-(2-fluoro-4-methoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E82-{[1-(4-bromo-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E92-{[1-(2-fluoro-4-methylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E102-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E11N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E12N-(2-methoxyethyl)-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E132-({1-[4-(4-chlorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E14N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4-methylphenoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E152-({1-[4-(4-tert-butylphenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E16N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E17N-(2-methoxyethyl)-2-({1-[4-(4-methoxyphenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E18N-(2-methoxyethyl)-4-methyl-2-{[1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E192-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E202-{[1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E212-{[1-(4-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E22N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E232-{[1-(2-methoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E24N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphonyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E25N-(2-methoxyethyl)-4-methyl-2-({1-[3-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E26N-(2-methoxyethyl)-4-methyl-2-{[1-(3-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E272-{[1-(3-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E282-({1-[4-(4-carbamoylphenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E292-({1-[4-(cyclopentyloxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E302-({1-[4-(difluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E312-{[1-(4-cyanobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E322-({1-[4-(1H-imidazol-1-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E33N-(2-methoxyethyl)-4-methyl-2-({1-[4-(oxazol-2-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E34N-(2-methoxyethyl)-4-methyl-2-({1-[4-(oxazol-5-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E35N-(2-methoxyethyl)-4-methyl-2-({1-[4-(isoxazol-5-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E36N-(2-methoxyethyl)-4-methyl-2-({1-[4-(1H-pyrazol-1-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E37N-(2-methoxyethyl)-4-methyl-2-({1-[4-(1H-1,2,4-triazol-1-yl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide;E382-({1-[4-(difluoromethoxy)-2-fluorobenzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E392-({1-[2-fluoro-4-(pyrrolidin-1-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E402-({1-[(3,4′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E412-({1-[(3-fluoro-4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E422-({1-[(3-fluoro-4′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide;E432-[(1-{[3-fluoro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E442-[(1-{[3-fluoro-2′-(trifluoromethoxy)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E452-({1-[(2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E462-({1-[(2′,4′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E472-({1-[(2-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E48N-(2-methoxyethyl)-4-methyl-2-({1-[(2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide;E49N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4-pyridyloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E50N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4H-1,2,4-triazol-4-yl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide;E512-({1-(2-fluoro-4-(morpholin-4-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E522-{[1-(4-bromobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E53N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide;E542-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E55N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E564-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E572-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E584-methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E592-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide;E60N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]-methyl}-2H-indazole-5-carboxamide;E61N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}-methyl)-4-methyl-2H-indazole-5-carboxamide;E62N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E63N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E642-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide;E652-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-carboxamide;E664-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-N-[2-(2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-carboxamide;E672-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide;E684-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E692-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide;E702-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoro-ethoxy)ethyl]-2H-indazole-5-carboxamide;E712-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E72N-(2-isopropoxyethyl)-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E732-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E74N-(2-isopropoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide;E752-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E762-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E772-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide;E782-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoro-methoxy)ethyl]-2H-indazole-5-carboxamide;E792-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoro-methoxy)ethyl]-2H-indazole-5-carboxamide;E804-methyl-N-[2-(trifluoromethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E81N-(2-tert-butoxyethyl)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carboxamide;E82N-(2-tert-butoxyethyl)-2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E83N-(2-tert-butoxyethyl)-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E84N-(2-tert-butoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E852-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-{2-[(²H3)methyloxy]-(²H4)ethyl}-2H-indazole-5-carboxamide;E862-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-{2-[(²H3)methyloxy](²H4)ethyl}-2H-indazole-5-carboxamide;E872-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E88N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide;E89N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide;E902-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E912-{[1-(4-chloro-2-fluorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E922-({1-[3-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E932-({1-[4-chloro-3-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E942-{[1-(4-cyclopropylbenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E95N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide;E962-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E974-methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}-methyl)-2H-indazole-5-carboxamide;E982-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E994-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]azetidin-3-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E100N-[2-(cyclopropyloxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide;E101N-[2-(cyclobutyloxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide;E1022-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide;E103N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}-methyl)-4-methyl-2H-indazole-5-carboxamide;E104N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzoyl)azetidin-3-yl]-methyl}-2H-indazole-5-carboxamide;E1052-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide;E106N-(2-tert-butoxyethyl)-2-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-2H-indazole-5-carboxamide;E107N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E1082-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1092-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E11 02-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1112-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1122-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-carboxamide;E1134-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide;E1144-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-azetidin-3-yl)methyl]-2H-indazole-5-carboxamide;E1152-({1-[4-(4-chlorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide;E1162-({1-[4-(4-chlorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E117N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)-azetidin-3-yl]methyl}-2H-indazole-5-carboxamide;E1184-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-benzoyl)azetidin-3-yl]methyl}-2H-indazole-5-carboxamide;E1192-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-ethyl-4-methyl-2H-indazole-5-carboxamide;E1202-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1212-({1-[4-(4-chlorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1224-methyl-2-({1-[4-(4-methylphenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1232-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1244-methyl-2-{[1-(4-morpholinobenzoyl)piperidin-4-yl]methyl}-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1254-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1264-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1274-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E1284-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E1294-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E1302-({1-[4-(4-cyanophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide;E1312-({1-[4-(3-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carboxamide;E1324-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1332-[(1-{4-[(5-cyanopyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1342-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1354-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[5-(trifluoromethyl)pyridin-2-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1362-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1372-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1384-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{[4′-(trifluoromethyl)biphenyl-4-yl]carbonyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1392-{[1-(4-bromobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1402-({1-[4-(5-chloropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1412-({1-[(4′-methoxy-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1424-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1432-({1-[(4′-fluoro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1444-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1452-({1-[4-(6-methoxypyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1462-({1-[4-(6-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1474-methyl-2-({1-[4-(5-methylpyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1482-({1-[4-(5-fluoropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1492-({1-[4-(5-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1504-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzoyl]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1514-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1524-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1532-({1-[4-(4-cyanophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1542-{[1-(4-bromo-3-methylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1552-{[1-(4-tert-butylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1562-({1-[4-(1-hydroxy-1-methylethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide;E1572-{[1-(4-cyclohexylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1582-({1-[4-(1-cyano-1-methylethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E159N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyrimidin-2-yloxy)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide;E160N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-3-yloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E161N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E162N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E163N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}-benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E164N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzoyl)-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E165N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E1662-({1-[(4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E167N-(2-methoxyethyl)-4-methyl-2-({1-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoyl]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E168N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1692-[(1-{4-[(5-cyanopyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide;E1702-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide;E1712-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1722-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E173N-(2-methoxyethyl)-4-methyl-2-[(1-{[4′-(trifluoromethyl)biphenyl-4-yl]carbonyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1742-({1-[4-(3-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1752-{[1-(2-fluoro-4-isopropoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1762-({1-[(3-fluoro-3′,4′-dimethylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1772-({1-[(2′,3-difluoro-4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1782-({1-[4-(difluoromethoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1792-({1-[4-(2-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1802-({1-[(4′-cyano-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1812-({1-[4-(5-chloropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E182N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E183N-(2-methoxyethyl)-2-({1-[(4′-methoxy-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E1842-({1-[(4′-chloro-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1852-[(1-{[4′-(2-cyanopropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E186N-(2-methoxyethyl)-2-({1-[4-(5-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E187N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E188N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E1892-({1-[(4′-fluoro-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E190N-(2-methoxyethyl)-4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide;E191N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E192N-(2-methoxyethyl)-4-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E1932-({1-[(4′-fluoro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1942-({1-[(4′-chloro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E195N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1962-({1-[(4′-chloro-2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide;E1972-({1-[(2′-chloro-4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide;E1982-({1-[4-(5-chloropyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1992-({1-[4-(5-fluoropyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E200N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[5-(trifluoromethyl)pyridin-3-yl]benzoyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E2012-[(1{[4′-(2-hydroxypropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E2022-({1-[(3′,5′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide;E2032-({1-[(4′-fluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide;E2042-({1-[(3′,5′-difluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E205N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(3-pyridyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide;E206N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(4-pyridyl)benzoyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide;and E207N-(2-methoxyethyl)-4-methyl-2-({1-[(2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide.6. The pharmaceutical composition of claim 5, where the EP2 receptorantagonist is selected from the group consisting of: E22-{[1-(4-tert-butoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E32-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E52-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E72-{[1-(2-fluoro-4-methoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E82-{[1-(4-bromo-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E92-{[1-(2-fluoro-4-methylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E102-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E11N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pentafluoro-λ⁶-sulphanyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E12N-(2-methoxyethyl)-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E132-({1-[4-(4-chlorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E14N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4-methylphenoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E152-({1-[4-(4-tert-butylphenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E16N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E17N-(2-methoxyethyl)-2-({1-[4-(4-methoxyphenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E18N-(2-methoxyethyl)-4-methyl-2-{[1-(4-phenoxybenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E192-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E202-{[1-(4-methoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E212-{[1-(4-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E22N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E24N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphonyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E25N-(2-methoxyethyl)-4-methyl-2-({1-[3-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E26N-(2-methoxyethyl)-4-methyl-2-{[1-(3-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E272-{[1-(3-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E292-({1-[4-(cyclopentyloxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E302-({1-[4-(difluoromethyl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E312-{[1-(4-cyanobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E36N-(2-methoxyethyl)-4-methyl-2-({1-[4-(1H-pyrazol-1-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E382-({1-[4-(difluoromethoxy)-2-fluorobenzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E392-({1-[2-fluoro-4-(pyrrolidin-1-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E402-({1-[(3,4′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E412-({1-[(3-fluoro-4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E422-({1-[(3-fluoro-4′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E432-[(1-{[3-fluoro-3′-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E442-[(1-{[3-fluoro-2′-(trifluoromethoxy)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E452-({1-[(2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E462-({1-[(2′,4′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E472-({1-[(2-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E48N-(2-methoxyethyl)-4-methyl-2-({1-[(2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E512-({1-[2-fluoro-4-(morpholin-4-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E522-{[1-(4-bromobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E53N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E542-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E55N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E592-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide;E60N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E61N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E62N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E63N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E642-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide;E652-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide;E664-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide;E672-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide;E684-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E692-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide;E702-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide;E712-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E72N-(2-isopropoxyethyl)-4-methyl-2-{[1-(4-methylbenzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E732-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E74N-(2-isopropoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E752-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E762-{[1-(4-cyclopropylbenzoyl)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E772-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide;E782-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide;E792-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide;E804-methyl-N-[2-(trifluoromethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E81N-(2-tert-butoxyethyl)-2-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carboxamide;E82N-(2-tert-butoxyethyl)-2-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E83N-(2-tert-butoxyethyl)-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E84N-(2-tert-butoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E852-{[1-(4-chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-{2-[(2H3)methyloxy](2H4)ethyl}-2H-indazole-5-carboxamide;E862-({1-[4-(4-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-{2-[(2H3)methyloxy](2H4)ethyl}-2H-indazole-5-carboxamide;E872-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E88N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide;E89N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide;E902-({1-[2-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E912-{[1-(4-chloro-2-fluorobenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E922-({1-[3-fluoro-4-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E932-({1-[4-chloro-3-(trifluoromethyl)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E942-{[1-(4-cyclopropylbenzoyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E95N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide;E100N-[2-(cyclopropyloxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide;E101N-[2-(cyclobutyloxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzoyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide;E1022-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide;E103N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E104N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzoyl)azetidin-3-yl]methyl}-2H-indazole-5-carboxamide;E1052-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide;E107N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E1082-({1-[(4′-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1092-({1-[4-(4-fluorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1122-{[1-(4-chlorobenzoyl)azetidin-3-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide;E1134-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide; E1144-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide;E1152-({1-[4-(4-chlorophenoxy)benzoyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1162-({1-[4-(4-chlorophenoxy)benzoyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E117N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)azetidin-3-yl]methyl}-2H-indazole-5-carboxamide;E1254-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1264-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1274-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E1284-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E1312-({1-[4-(3-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1324-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1372-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1384-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{[4′-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1412-({1-[(4′-methoxy-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1432-({1-[(4′-fluoro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide;E1532-({1-[4-(4-cyanophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1542-{[1-(4-bromo-3-methylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1552-{[1-(4-tert-butylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1572-{[1-(4-cyclohexylbenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E160N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-3-yloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E161N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E162N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-2-yloxy)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E163N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E164N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E165N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluormethyl)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide;E1662-({1-[(4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E168N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1702-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzoyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1712-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1722-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E173N-(2-methoxyethyl)-4-methyl-2-[(1-{[4′-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1742-({1-[4-(3-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1752-{[1-(2-fluoro-4-isopropoxybenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1762-({1-[(3-fluoro-3′,4′-dimethylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1772-({1-[(2′,3-difluoro-4′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1782-({1-[4-(difluoromethoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1792-({1-[4-(2-fluorophenoxy)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1802-({1-[(4′-cyano-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1812-({1-[4-(5-chloropyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E182N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E183N-(2-methoxyethyl)-2-({1-[(4′-methoxy-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E1842-({1-[(4′-chloro-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1852-[(1-{[4′-(2-cyanopropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E186N-(2-methoxyethyl)-2-({1-[4-(5-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E187N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E188N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E1892-({1-[(4′-fluoro-2′-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E190N-(2-methoxyethyl)-4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E191N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-2-yl)benzoyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide;E1932-({1-[(4′-fluoro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1942-({1-[(4′-chloro-2′-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E195N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1962-({1-[(4′-chloro-2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1972-({1-[(2′-chloro-4′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1982-({1-[4-(5-chloropyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E1992-({1-[4-(5-fluoropyridin-3-yl)benzoyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E200N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[5-(trifluoromethyl)pyridin-3-yl]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E2012-[(1-{[4′-(2-hydroxypropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E2022-({1-[(3′,5′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E2032-({1-[(4′-fluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E2042-({1-[(3′,5′-difluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide;E205N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(3-pyridyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;E206N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(4-pyridyl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide;and E207N-(2-methoxyethyl)-4-methyl-2-({1-[(2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide.7. The pharmaceutical composition off claim 6, where the EP2 receptorantagonist is selected from the group consisting of: E16N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;E1264-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide;and E161N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide.8. The pharmaceutical composition of claim 2, wherein the COX inhibitoris in a dose range selected from: C1 indomethacin: 19-800 mg/day; C2diclofenac: 37.5-800 mg/day; C4 naproxen: 125-4000 mg/day; C5 ibuprofen:200-4800 mg/day; C6 meloxicam: 2-60 mg/day; C7 piroxicam: 5-80 mg/day;C8 nimesulide: 25-800 mg/day; C9 ketoprofen: 25-1200 mg/day; C10tenoxicam: 10-160 mg/day; C11 mefanemic acid: 125-2000 mg/day; C12ketoralac: 2.5-160 mg/day; C13 celecoxib: 25-800 mg/day; C14 parecoxib12.5-200 mg/day; C15 rofecoxib: 6-200 mg/day; C16 valdecoxib: 10-160mg/day; and C17 etoricoxib: 15-360 mg/day.
 9. Pharmaceutical compositionaccording to any of claims 2-7, where the COX inhibitor is C1indomethacin; C2 diclofenac; C4 naproxen; C5 ibuprofen; C6 meloxicam; C7piroxicam; or C8 nimesulide.
 10. The pharmaceutical composition of claim9, where the COX inhibitor is: C1 indomethacin; C2 diclofenac; C6meloxicam; or C7 piroxicam.
 11. A method of contraception comprisingadministering the pharmaceutical composition of claim 1 to a woman in asingle administration dose in a period of up to 24 hours, preferably6-12 hours, before expected sexual intercourse or up to 2 hours aftersexual intercourse.
 12. A method of on-demand contraception, comprisingadministering the pharmaceutical composition according to claim 2 to awoman on demand and once in a period of 0-24, preferably 6-12, hoursprior to expected sexual intercourse or up to 2 hours after sexualintercourse.
 13. A method of on-demand contraception, comprisinginitially taking a first pharmaceutical composition according to claim 2in a period of up to 24 hours, prior to expected sexual intercourse, andtaking a second pharmaceutical composition according to claim 2 in aperiod of up to 48 hours after sexual intercourse, where thepreparations taken before and after intercourse are identical.
 14. Amethod of on-demand contraception, comprising initially taking a firstpharmaceutical composition according to claim 2 in a period of up to 24hours, prior to expected sexual intercourse, and taking a secondpharmaceutical composition according to claim 2 in a period of up to 48hours after sexual intercourse, where the preparations taken before andafter intercourse are not identical.
 15. An administration protocol foron-demand contraception, characterized in that a pharmaceuticalcomposition according to claim 2 is taken in a period of up to 24 hours,preferably 6-12 hours, prior to expected sexual intercourse and afurther pharmaceutical composition according to claim 2 is taken in aperiod of up to 48 hours after sexual intercourse.
 16. A kit forproviding an administration protocol according to claim 15 or forcarrying out the method of claim 13 of on-demand contraception,comprising at least one tablet comprising a pharmaceutical compositionaccording to claim 2, for administration before, and at least one tabletcomprising a pharmaceutical composition according to claim 2, foradministration after expected sexual intercourse.
 17. The pharmaceuticalcomposition of claim 2, wherein the pharmaceutical composition is in theform of a pharmaceutical preparation for oral, pulmonary, nasal, dermalor transdermal administration.
 18. The pharmaceutical composition ofclaim 1, wherein X is —(CH₂)_(l)— where l is; and R⁴ is additionally a4-6-membered heterocyclyl radical linked via a ring carbon atom.
 19. Akit for carrying out the method of claim 14 of on-demand contraception,comprising at least one tablet comprising a pharmaceutical compositionaccording to claim 2, for administration before, and at least one tabletcomprising a pharmaceutical composition according to claim 2, foradministration after expected sexual intercourse.